Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

The influence of maternal Lewis, Secretor and ABO(H) blood groups on fetal growth restriction.

BACKGROUND: Fetal growth restriction (FGR) is associated with thrombosis of the placenta and an increased risk of subsequent vascular disease in the mother and fetus. The products of interactions between ABO(H), Lewis and Secretor genes are also associated with thrombosis and vascular disease risk. OBJECTIVES/METHODS: A prospective case-control study of mothers with a severe FGR pregnancy (cases, n = 128; controls, n = 288) was performed to determine whether FGR is associated with particular maternal blood groups. RESULTS: No association with ABO(H) status was observed, but FGR was more common in maternal secretors (odds ratio [OR] 1.70, 95% confidence interval [CI] 1.08-2.69) and consequently in those mothers expressing Le(b) on their red cells (OR 1.80, 95% CI 1.15-2.83), with a reduced risk in non-secretors and those expressing Le(a). Given the association between blood groups and both activated protein C resistance (APCR) and von Willebrand factor (VWF) levels, post hoc pilot studies on first-trimester APCR and VWF antigen levels and blood group genotypes were performed. No relationship with Lewis or Secretor was observed. Despite this, lower first-trimester VWF levels were observed in pregnancies subsequently complicated by FGR. CONCLUSIONS: This is the first study reporting a relationship between maternal Secretor/Lewis status and FGR. A link between blood groups and FGR is plausible, as both are associated with cardiovascular disease. We observed no relationship between Lewis/Secretor status and VWF or APCR, but this should be confirmed in a larger study. Thus, the mechanism whereby Secretor and/or Lewis influences FGR is unknown.

Antithrombotic treatment for recurrent pregnancy loss?

BACKGROUND: Recurrent pregnancy loss (RPL) is a major issue for women's health. Acquired and heritable thrombophilias are associated with RPL, this association could reflect a general prothrombotic phenotype rather than a specific thrombophilia. Antithrombotic intervention has therefore been assessed for RPL. RESULTS: Two large randomised trials with untreated control groups showed no benefit from antithrombotic treatment with LMWH and low dose aspirin in women with RPL. These trials had insufficient power to exclude an effect in women with underlying thrombophilia, ≥ 3 losses, or late losses. CONCLUSIONS: Antithrombotic intervention should not be recommended for unexplained RPL in general. There may be specific groups such as those with an heritable thrombophilia, or with three or more losses, or second trimester losses that might benefit and where further trials are required. Further there is a need to consider the benefits of LMWH on implantation such as in women undergoing assisted conception therapy.

Fetal corticotrophin-releasing hormone mRNA, but not phosphatidylserine-exposing microparticles, in maternal plasma are associated with factor VII activity in pre-eclampsia.

BACKGROUND: Pre-eclampsia is associated with increased placental debris circulating in maternal plasma. OBJECTIVES: This study related placental debris to maternal markers of coagulation and endothelial activation in pre-eclampsia. PATIENTS/METHODS: Circulating fetal corticotrophin-releasing hormone (CRH) mRNA and phosphatidylserine (PS)-exposing microparticles were assayed in third trimester plasma from women with pre-eclampsia (n = 32) and controls (n = 32) matched for age, body mass index, parity, and gestational age at sampling. Markers of maternal hemostasis and endothelial function were assessed. RESULTS: Fetal CRH mRNA levels were higher in pre-eclampsia [mean 0.75 (SD 2.77) CRH/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio] than in control pregnancies [0.20 (0.74), P = 0.014]. PS-exposing microparticle levels were not different between the groups. Women with pre-eclampsia had higher levels of tissue factor pathway inhibitor (TFPI), prothrombin F(1+2) fragment (F(1+2)), factor XIIa, soluble vascular cell adhesion molecule 1, von Willebrand factor and plasminogen activator inhibitor 1 than controls. Fetal CRH mRNA correlated with TFPI in pre-eclampsia and control groups (r = 0.38, P = 0.031, and r = 0.37, P = 0.039, respectively). Fetal CRH mRNA correlated with FVII activity (r = 0.43, P = 0.017) and PS-exposing microparticles correlated inversely with F(1+2) (r = -0.64, P < 0.001) in pre-eclampsia. CONCLUSIONS: Placental debris, assessed by fetal CRH mRNA levels in maternal blood, is related to coagulation potential, i.e. FVII activity, but not to markers of coagulation or endothelial activation in pre-eclampsia.

The parturient with coronary heart disease.

Cardiac disease is one of the leading indirect causes of maternal mortality in the UK, exceeding numbers of direct deaths from thromboembolism and hypertension combined. Over one year in our unit we managed six women with coronary heart disease. In this series five women had stable coronary heart disease. Three delivered electively by caesarean section under combined spinal-epidural anaesthesia, a further two women had spontaneous vaginal deliveries, one planned under epidural analgesia, the second unplanned after a rapid labour. The sixth woman had unstable angina requiring percutaneous coronary intervention in the 28th week of pregnancy and went on to deliver by caesarean section under general anaesthesia. Regional anaesthesia was avoided in this case because of antiplatelet and anticoagulant medication. There is a lack of level-one evidence to direct the management of these women. Clinical decisions were directed by guidelines for the perioperative management of patients with cardiac disease in non-cardiac surgery and the management of all cardiac disease in the obstetric population. A multi-disciplinary approach was taken, with a collaborative plan made for each pregnancy and delivery. A thorough clinical history and examination together with transthoracic echocardiography allows risk stratification of women with coronary heart disease at risk of peripartum cardiac events. Further investigation specific to each woman's management can then be undertaken.

Social inequalities in preterm birth in Scotland 1980-2003: findings from an area-based measure of deprivation.

OBJECTIVE: The preterm birth rate in Scotland has been increasing in recent years. Although preterm birth rates show a social gradient, it is unclear how this gradient has been affected by the overall increase. We examined time trends in singleton live preterm birth rates in relation to area-based socio-economic indicators. DESIGN: Population-based retrospective cohort study. SETTING: Scotland. PARTICIPANTS: All singleton live births delivered in Scottish hospitals between 1980 and 2003 (n= 1 423 993). MAIN OUTCOME MEASURES: Singleton live preterm birth rates in each deprivation quintile were derived. Subgroup analyses of those born moderately preterm (32-36 weeks), very preterm (28-31 weeks) and extremely preterm (24-27 weeks) were performed. RESULTS: The rate of singleton live preterm births increased from 49.7 per 1000 live births in the 5-year period 1980-84 to 56.1 per 1000 in the 4-year period 2000-03, a relative increase of 12.9%. A marked social gradient was apparent at all time periods: relative indices of inequality were 1.63 (95% CI 1.38-1.92) in 1980-84 and 1.55 (1.44-1.66) in 2000-03. Similar social gradients existed for all gestational age subgroups. Smoking status at first antenatal contact and increased obstetric intervention, possibly reflecting improvements in fetal monitoring and neonatal care, appeared to explain some but not all the social gradient. CONCLUSIONS: Social inequalities in preterm birth were apparent in Scotland between 1980 and 2003. In addition to helping pregnant women to stop smoking, other means to reduce social inequalities are required.

Gestational related changes in the deep venous system of the lower limb on light reflection rheography in pregnancy and the puerperium.

OBJECTIVE: To assess whether light reflection rheography testing is affected by the changes that occur in the deep venous system of the lower limb in pregnancy and the puerperium. METHODS: Twenty five women with a singleton pregnancy were recruited to undergo duplex Doppler ultrasound examinations of the common femoral vein to measure the vessel diameter and the blood flow velocity. Light reflection rheography testing was subsequently performed and the rate of venous emptying in the lower limb calculated. Serial measurements using both techniques were made at 15, 28, 36 weeks, and term gestation and at 2 days and 6 weeks postpartum. RESULTS: Duplex Doppler ultrasound confirmed that there is progressive dilatation of the deep venous system in pregnancy, which reaches a maximum at term and reverses after delivery. There is an accompanying reduction in blood flow velocity, which reaches a nadir at term and increases after delivery. The rate of venous emptying as measured by light reflection rheography decreases with increasing gestation, but did not fall to a level consistent with venous occlusion by a deep venous thrombosis. CONCLUSIONS: Light reflection rheography has been shown to provide reliable results in pregnancy and the puerperium. Therefore, it is a potential tool for screening for deep venous thrombosis in this population.

Intra- and interlaboratory variability in acute toxicity tests with glochidia and juveniles of freshwater mussels (Unionidae).

The present study evaluated the performance and variability in acute toxicity tests with glochidia and newly transformed juvenile mussels using the standard methods outlined in American Society for Testing and Materials (ASTM). Multiple 48-h toxicity tests with glochidia and 96-h tests with juvenile mussels were conducted within a single laboratory and among five laboratories. All tests met the test acceptability requirements (e.g., >or=90% control survival). Intralaboratory tests were conducted over two consecutive mussel-spawning seasons with mucket (Actinonaias ligamentina) or fatmucket (Lampsilis siliquoidea) using copper, ammonia, or chlorine as a toxicant. For the glochidia of both species, the variability of intralaboratory median effective concentrations (EC50s) for the three toxicants, expressed as the coefficient of variation (CV), ranged from 14 to 27% in 24-h exposures and from 13 to 36% in 48-h exposures. The intralaboratory CV of copper EC50s for juvenile fatmucket was 24% in 48-h exposures and 13% in 96-h exposures. Interlaboratory tests were conducted with fatmucket glochidia and juveniles by five laboratories using copper as a toxicant. The interlaboratory CV of copper EC50s for glochidia was 13% in 24-h exposures and 24% in 48-h exposures, and the interlaboratory CV for juveniles was 22% in 48-h exposures and 42% in 96-h exposures. The high completion success and the overall low variability in test results indicate that the test methods have acceptable precision and can be performed routinely.

Chronic toxicity of copper and ammonia to juvenile freshwater mussels (Unionidae).

The objectives of the present study were to develop methods for conducting chronic toxicity tests with juvenile mussels under flow-through conditions and to determine the chronic toxicity of copper and ammonia to juvenile mussels using these methods. In two feeding tests, two-month-old fatmucket (Lampsilis siliquoidea) and rainbow mussel (Villosa iris) were fed various live algae or nonviable algal mixture for 28 d. The algal mixture was the best food resulting in high survival (>or=90%) and growth. Multiple copper and ammonia toxicity tests were conducted for 28 d starting with two-month-old mussels. Six toxicity tests using the algal mixture were successfully completed with a control survival of 88 to 100%. Among copper tests with rainbow mussel, fatmucket, and oyster mussel (Epioblasma capsaeformis), chronic value ([ChV], geometric mean of the no-observed-effect concentration and the lowest-observed-effect concentration) ranged from 8.5 to 9.8 microg Cu/L for survival and from 4.6 to 8.5 microg Cu/L for growth. Among ammonia tests with rainbow mussel, fatmucket, and wavy-rayed lampmussel (L. fasciola), the ChV ranged from 0.37 to 1.2 mg total ammonia N/L for survival and from 0.37 to 0.67 mg N/L for growth. These ChVs were below the U.S. Environmental Protection Agency 1996 chronic water quality criterion (WQC) for copper (15 microg/L; hardness 170 mg/L) and 1999 WQC for total ammonia (1.26 mg N/L; pH 8.2 and 20 degrees C). Results indicate that toxicity tests with two-month-old mussels can be conducted for 28 d with >80% control survival; growth was frequently a more sensitive endpoint compared to survival; and the 1996 chronic WQC for copper and the 1999 chronic WQC for total ammonia might not be adequately protective of the mussel species tested. However, a recently revised 2007 chronic WQC for copper based on the biotic ligand model may be more protective in the water tested.

Sensitivity of mottled sculpins (Cottus bairdi) and rainbow trout (Onchorhynchus mykiss) to acute and chronic toxicity of cadmium, copper, and zinc.

Studies of fish communities of streams draining mining areas suggest that sculpins (Cottus spp.) may be more sensitive than salmonids to adverse effects of metals. We compared the toxicity of zinc, copper, and cadmium to mottled sculpin (C. bairdi) and rainbow trout (Onchorhynchus mykiss) in laboratory toxicity tests. Acute (96-h) and early life-stage chronic (21- or 28-d) toxicity tests were conducted with rainbow trout and with mottled sculpins from populations in Minnesota and Missouri, USA, in diluted well water (hardness = 100 mg/L as CaCO3). Acute and chronic toxicity of metals to newly hatched and swim-up stages of mottled sculpins differed between the two source populations. Differences between populations were greatest for copper, with chronic toxicity values (ChV = geometric mean of lowest-observed-effect concentration and no-observed-effect concentration) of 4.4 microg/L for Missouri sculpins and 37 microg/L for Minnesota sculpins. Cadmium toxicity followed a similar trend, but differences between sculpin populations were less marked, with ChVs of 1.1 microg/L (Missouri) and 1.9 microg/L (Minnesota). Conversely, zinc was more toxic to Minnesota sculpins (ChV = 75 microg/L) than Missouri sculpins (chronic ChV = 219 microg/L). Species-average acute and chronic toxicity values for mottled sculpins were similar to or lower than those for rainbow trout and indicated that mottled sculpins were among the most sensitive aquatic species to toxicity of all three metals. Our results indicate that current acute and chronic water quality criteria for cadmium, copper, and zinc adequately protect rainbow trout but may not adequately protect some populations of mottled sculpins. Proposed water quality criteria for copper based on the biotic ligand model would be protective of both sculpin populations tested.

The effect of graduated compression stockings on blood velocity in the deep venous system of the lower limb in the postnatal period.

Venous thromboembolism (VTE) is the leading cause of maternal mortality in the UK and is also a major cause of long-term morbidity. Recent UK national guidelines recommend thromboprophylaxis, which includes the use of graduated compression stockings (GCS), for high-risk women to reduce the risk of VTE in both the antenatal and postpartum period. This study of 17 women examined the effects of GCS on the deep venous system in the immediate postpartum period and found a statistically significant reduction in the diameter of the common femoral vein (CFV) (pre- versus post stocking diameter: mean 10.39 mm [SD 2.09] versus mean 9.69 mm [SD 1.99]) and an increase in the rate of blood velocity in the CFV (pre- versus post stocking velocity: mean 10.0 cm/s [SD 2.7] versus 13.9 cm/s [SD 4.2]) 30 minutes after application of thigh length GCS in women 1 or 2 days following a singleton vaginal delivery at term. This confirms reduction in venous stasis in the deep venous system in the immediate postpartum woman by the use of GCS, supporting their use in improving venous function in this context.

Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

OBJECTIVES: To assess the risk of clinical complications associated with thrombophilia in three high-risk patient groups: women using oral oestrogen preparations, women during pregnancy and patients undergoing major orthopaedic surgery. To assess the effectiveness of prophylactic treatments in preventing venous thromboembolism (VTE) and adverse pregnancy outcomes in women with thrombophilia during pregnancy and VTE in patients with thrombophilia, undergoing major orthopaedic surgery. To evaluate the relative cost-effectiveness of universal and selective VTE history-based screening for thrombophilia compared with no screening in the three high-risk patient groups. DATA SOURCES: Electronic databases including MEDLINE, EMBASE, and four other major databases were searched up to June 2003. REVIEW METHODS: In order to assess the risk of clinical complications associated with thrombophilia, a systematic review of the literature on VTE and thrombophilia in women using oral oestrogen preparations and patients undergoing major orthopaedic surgery; and studies of VTE and adverse obstetric complications in women with thrombophilia during pregnancy was carried out. Meta-analysis was used to calculate pooled odds ratios (ORs) associated with individual clinical outcomes, stratified by thrombophilia type and were calculated for each patient group. To assess the effectiveness of prophylaxis, a systematic review was carried out on the use of prophylaxis in the prevention of VTE and pregnancy loss in pregnant women with thrombophilic defects and the use of thromboprophylaxis in the prevention of VTE in patients with thrombophilia undergoing major elective orthopaedic surgery. Relevant data were summarised according to the patient groups and stratified according to the types of prophylaxis. A narrative summary was provided; where appropriate, meta-analysis was conducted. An incremental cost-effectiveness analysis was then carried out, from the perspective of the NHS in the UK. A decision analytical model was developed to simulate the clinical consequences of four thrombophilia screening scenarios. Results from the meta-analyses, information from the literature and results of two Delphi studies of clinical management of VTE and adverse pregnancy complications were incorporated into the model. Only direct health service costs were measured and unit costs for all healthcare resources used were obtained from routinely collected data and the literature. Cost-effectiveness was expressed as incremental cost-effectiveness ratios (ICERs); an estimate of the cost per adverse clinical complication prevented, comparing screening with no screening, were calculated for each patient group. RESULTS: In the review of risk of clinical complications, 81 studies were included, nine for oral oestrogen preparations, 72 for pregnancy and eight for orthopaedic surgery. For oral contraceptive use, significant associations of the risk of VTE were found in women with factor V Leiden (FVL); deficiencies of antithrombin, protein C, or protein S, elevated levels of factor VIIIc; and FVL and prothrombin G20210A. For hormone replacement therapy (HRT), a significant association was found in women with FVL. The highest risk in pregnancy was found for FVL and VTE, in particular, homozygous carriers of this mutation are 34 times more likely to develop VTE in pregnancy than non-carriers. Significant risks for individual thrombophilic defects were also established for early, recurrent and late pregnancy loss; preeclampsia; placental abruption; and intrauterine growth restriction. Significant associations were found between FVL and high factor VIIIc and postoperative VTE following elective hip or knee replacement surgery. Prothrombin G20210A was significantly associated with postoperative pulmonary embolism. However, antithrombin deficiency, MTHFR and hyperhomocysteinaemia were not associated with increased risk of postoperative VTE. In the review of the effectiveness of prophylaxis, based on available data from eight studies, low-dose aspirin and heparin was found to be the most effective in preventing pregnancy loss in thrombophilic women during pregnancy, while aspirin alone was the most effective in preventing minor bleeding. All the studies on thrombophilia and major elective orthopaedic surgery included in the review of risk complications were also used in the review of the effectiveness of thromboprophylaxis. However, there were insufficient data to determine the relative effectiveness of different thromboprophylaxis in preventing VTE in this patient group. For the cost-effectiveness analysis, of all the patient groups evaluated, universal screening of women prior to prescribing HRT was the most cost-effective (ICER pound6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER pound202,402). Selective thrombophilia screening based on previous personal and/or family history of VTE was more cost-effective than universal screening in all the patient groups evaluated. CONCLUSIONS: Thrombophilia is associated with increased risks of VTE in women taking oral oestrogen preparations and patients undergoing major elective orthopaedic surgery, and of VTE and adverse pregnancy outcomes in women with thrombophilia during pregnancy. There is considerable difference in the magnitude of the risks among different patient groups with different thrombophilic defects. In women who are on combined oral contraceptives, the OR of VTE among those who are carriers of the FVL mutation was 15.62 (95% confidence interval 8.66 to 28.15). However, in view of the prevalence of thrombophilia and the low prevalence of VTE in non-users of combined oral contraceptives, the absolute risk remains low. Significant risks for VTE and adverse pregnancy outcomes have been established with individual thrombophilic defects. Thrombophilic defects including FVL, high plasma factor VIIIc levels and prothrombin G20210A are associated with the occurrence of postoperative VTE in elective hip or knee replacement therapy. These associations are observed in patients who were given preoperative thromboprophylaxis and are, therefore, of clinical significance. Universal thrombophilia screening in women prior to prescribing oral oestrogen preparations, in women during pregnancy and in patients undergoing major orthopaedic surgery is not supported by current evidence. The findings from this study show that selective screening based on prior VTE history is more cost-effective than universal screening. Large prospective studies should be undertaken to refine the risks and establish the associations of thrombophilias with VTE among hormone users and in patients undergoing orthopaedic surgery. The relative value of a thrombophilia screening programme to other healthcare programmes needs to be established.

Thrombophilia in pregnancy: a systematic review.

Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0.74-34.40); early pregnancy loss (ORs, 1.40-6.25); late pregnancy loss (ORs, 1.31-20.09); pre-eclampsia (ORs, 1.37-3.49); placental abruption (ORs, 1.42-7.71) and intrauterine growth restriction (ORs, 1.24-2.92). Low-dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1.62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.

The role of factor V Leiden in maternal health and the outcome of pregnancy.

There is growing evidence that women with thrombophilia are at increased risk of pregnancy related venous thromboembolism and of adverse pregnancy outcome including pregnancy loss, pre-eclampsia, intrauterine growth retardation and placental abruption. The factor V Leiden mutation is a heritable thrombophilia present in 5-8% of Caucasian populations. In its heterozygous form it is associated with a 4-to 8-fold increase in thrombotic risk. Homozygous inheritance, however, confers around an 80-fold increase in relative risk of thrombosis. The relationship between factor V Leiden and adverse pregnancy outcome has been studied in the recent literature, however the size of the estimated risks varies between individual studies due to heterogeneity of study design and small sample size in many cases. The management of women with factor V Leiden in pregnancy with low molecular weight heparin has been shown to be both safe and effective in preventing venous thromboembolism and improving pregnancy loss. Large scale, randomised controlled studies are required to confirm these findings. Selective screening for factor V Leiden based on prior venous thromboembolism has been shown to be marginally more cost-effective than universal screening in pregnancy and a recent consensus statement has recommended screening for thrombophilia based on a strong personal or family history of venous thromboembolism. There is now some evidence that placental problems may be associated with factor V Leiden in the fetus. There has also been an observed association between maternal factor V Leiden and fetal or neonatal stroke. These areas require further study and at present there is no evidence-based approach to investigation, prevention or management.