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 use of intrapartum electronic fetal heart rate monitoring: a national survey.

This study describes the use of intrapartum electronic fetal monitoring in Ireland. Electronic fetal monitoring (EFM) has become routine in the assessment of fetal wellbeing during labour. Current evidence indicates that the routine use of EFM leads to an increased caesarean section and operative vaginal delivery rate and a reduction in the rate of neonatal seizures. Practices and service provision related to the use and interpretation of and educational provision for electronic fetal monitoring have not been investigated in Ireland. A national survey of all (n = 22) maternity units in Ireland was undertaken using a self-reported questionnaire amended, with permission, from that used in the 8th CESDI report. The questionnaire sought information on unit birth rate in 2002, number of cardiotocograph (CTG) monitors available in delivery units, use of the admission CTG, use of continuous EFM for women with various risk factors for pregnancy and/or labour, availability of fetal blood sampling facilities, use of umbilical cord blood sampling and availability of guidelines on the use of EFM. All units responded to the survey giving a national picture of the use of EFM during labour. All units had cardiotocograph (CTG) monitors available in the delivery area (median 6, range 3-14). An admission CTG was performed on all women by 96% (n=21) of units. Thirty six per cent of units (n=8) used continuous EFM routinely during labour in women who did not have risk factors for labour. Fetal blood sampling (FBS) was used in 36% (n=8) of units in cases of suspicious CTG tracings. Umbilical cord blood gases were sampled routinely following emergency caesarean section in 46% (n= 10) of units while 64% (n= 14) did so if the baby's condition was poor at birth. A departmental guideline on the use of EFM was available in 73% (n= 16) units. The findings of this survey indicate wide variations in the use of intrapartum EFM in Ireland. The use of continuous EFM for specific high-risk indications was variable and EFM was used by a third of units for women who did not have risk factors for labour. The admission CTG was used by 21 of the 22 units despite evidence of no benefit. The absence of FBS in the majority of units surveyed and the low rate of umbilical cord blood sampling is of concern.

Potential predictors of chemotherapy response in ovarian cancer--how do we define chemosensitivity?

OBJECTIVE: The aim of this study was to assess whether microvessel density (measured by CD31), vascular endothelial growth factor (VEGF) or multidrug resistance (MDR1) could determine the response to chemotherapy or act as prognostic factors in ovarian cancer. METHODS: Seventy-nine ovarian specimens were immunostained. Pearson correlation, 1-way ANOVA and chi-square were used for univariate analysis. Kaplan Meier survival curves were used, log-rank was used for univariate analysis and a Cox proportional hazards regression model was used for multivariate evaluation. Response to chemotherapy was assessed after 6 months and again after 1 year. RESULT: Quantifying VEGF proved to be a valuable independent prognostic indicator in progression-free survival (PFS) (p<0.05) and overall survival (OS) (p<0.0001). VEGF correlated with response to chemotherapy at the 6-month interval (r=0.446, p<0.001) but failed to correlate at the 1-year interval. Increased staining with CD31 was associated with decreased PFS (p<0.01) and OS (p<0.01) in univariate but not multivariate analysis. MDR1 failed to act as a prognostic marker or as a predictor of response to chemotherapy. CONCLUSION: VEGF correlates with response to chemotherapy at the 6-month but not the 12-month interval. What should our criteria be for determining sensitivity to chemotherapy? CD31, VEGF and MDR1 do play a role in some ovarian malignancies but other factors are likely to be involved and perhaps molecular profiling will determine which factors will be important for determining the response to chemotherapy.

Haemostatic risk factors in healthy postmenopausal women taking hormone replacement therapy.

OBJECTIVE: To compare changes in haemostatic parameters in healthy postmenopausal women taking either tibolone or 17beta-oestradiol/norethisterone acetate. METHODS: Factor VIIc, antithrombin, fibrinogen, thrombin-antithrombin complex (TAT), FDP (D-Dimer), tissue plasminogen activator (tPA) and plasminogen activator inhibitor I (PAI-1) were measured in 80 healthy postmenopausal women after 3, 6 and 12 months therapy with either 17beta-oestradiol/norethisterone acetate or tibolone. RESULTS: Both treatments significantly reduced fibrinogen, factor VIIc, antithrombin, tPA and PAI-1 antigen. Significantly lower levels of factor VIIc activity were observed on treatment with tibolone compared with 17beta-oestradiol/norethisterone acetate. TAT was unchanged with both treatments as was tPA activity. FDP (D-dimer) was increased on treatment with both preparations. CONCLUSIONS: The enhanced fibrin turnover and reduced antithrombin activity may play a role in the increased risk of venous thromboembolism in some susceptible women taking hormone replacement therapy (HRT) and could explain the lack of benefit of HRT in the secondary prevention of cardiovascular disease. The decreased levels of fibrinogen and factor VIIc found during treatment with 17beta-oestradiol/norethisterone acetate or tibolone may offer some degree of cardioprotection in healthy woman without pre-existing disease.

von Willebrand's disease: an important cause of dysfunctional uterine bleeding.

We assessed the prevalence of von Willebrand's disease (VWD) in patients with objectively confirmed dysfunctional uterine bleeding. A case-control study was designed to include 38 patients with objectively confirmed dysfunctional uterine bleeding and 38 age-matched controls with normal menstrual blood loss (MBL). Menorrhagia was defined as a mean MBL of greater than 80 ml on three consecutive menses as measured by the alkali haematin method. von Willebrand factor antigen, von Willebrand factor activity (VWF:Ac) and factor VIII:C were measured on three serial venous blood samples 1 week apart. VWD was diagnosed in five of 38 (13%) patients with menorrhagia and one of 38 (2.6%) patients with normal menstrual blood loss. The mean VWF:Ac value was significantly reduced in patients with menorrhagia (mean +/- standard deviation, 84.5 +/- 26.7 IU/dl versus 103.9 +/- 34.5 IU/dl; P < 0.01) and this effect persisted after exclusion of patients diagnosed with VWD. Failure to investigate patients for VWD will limit the potential benefits of medical therapies such as tranexamic acid or nasal desmopressin [1-desamino-8-D-arginine vasopressin, (DDAVP)] and, in addition, will lead to an increased risk associated with surgical intervention in patients with undiagnosed VWD.

Serous papillary adenocarcinomas of the ovary display heterogeneity in their response to chemotherapy.

The response of ovarian serous papillary adenocarcinomas to various cytotoxic drugs was examined using the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) cytotoxicity assay. Thirty tumors were collected and organized into four groups according to histologic grade and FIGO stage: stage III, grade 2; stage III, grade 3; stage IV, grade 2; and stage IV, grade 3. The MTS chemosensitivity assay was performed on each tumor to examine the response to cisplatin, paclitaxel, hycamtin and the combination of cisplatin and paclitaxel. Ovarian adenocarcinomas of similar stage and grade displayed varying responses to the same drug. A lower concentration of the drug was often as effective as the peak plasma concentration. For some specimens combination therapy was more effective for inhibiting tumor growth, and for others single-agent therapy gave a better response. A chemosensitivity/resistance profile is recommended before deciding on appropriate chemotherapy.

Differential effects of raloxifene and continuous combined hormone replacement therapy on biochemical markers of cardiovascular risk: results from the Euralox 1 study.

OBJECTIVE: To compare the effects of the selective estrogen receptor modulator (SERM) raloxifene (Evista) and a continuous combined hormone replacement therapy (ccHRT) formulation containing estradiol and norethisterone acetate (Kliogest) on lipid and fibrinogen levels of postmenopausal women. METHODS: Euralox 1 was a prospective, randomized, double-blind trial. After a placebo wash-out, healthy postmenopausal women (n = 1008, average age 56.1 +/- 4.9 years) with a health risk profile that suggested a potential benefit from either treatment were randomly assigned to either 60 mg raloxifene or ccHRT consisting of 2 mg estradiol and 1 mg norethisterone acetate (NETA) per day for 6 months. MEASUREMENTS: Total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol with its fractions HDL2 and HDL3, the LDL/HDL ratio, triglycerides and fibrinogen were assessed at baseline and after 6 months or on early drop-out. RESULTS: Baseline values were comparable between the two groups. Blood samples of 841 women (83.4%) were available at baseline and endpoint. Total and LDL cholesterol decreased statistically significantly from baseline to endpoint in both treatment arms (by 7.2% and 3.8% with raloxifene and by 13.0% and 8.9% with ccHRT, respectively). Raloxifene produced a statistically significant increase in HDL cholesterol by 4.2%, while ccHRT induced a decline by 9.5%. Triglycerides were moderately suppressed with raloxifene and ccHRT, by 3.6 and 5.4%, respectively. Fibrinogen fell by 7.0% with raloxifene and rose by 3.6% with ccHRT. CONCLUSIONS: Continuous combined HRT was associated with decreases in total cholesterol and LDL cholesterol about twice as large as with raloxifene, but also with a decrease in HDL cholesterol. The smaller decreases in total cholesterol and LDL cholesterol associated with raloxifene were accompanied by an increase in HDL cholesterol and a decrease in fibrinogen. In conclusion, raloxifene affects fibrinogen concentrations and the overall cholesterol profile more favorably than ccHRT; these differences may have important implications for the reduction of cardiovascular disease.

Massive obstetric haemorrhage.

Massive obstetric haemorrhage is a major cause of maternal death and morbidity; abruptio placentae, placenta praevia and postpartum haemorrhage being the main causes. A delay in the correction of hypovolaemia, a delay in the diagnosis and treatment of defective coagulation and a delay in the surgical control of bleeding are the avoidable factors in most maternal deaths caused by haemorrhage. The degree of hypotension is the first guide to the level of blood loss, except in abruptio placentae. A protocol incorporating the guidelines is shown. The rapid correction of hypovolaemia with crystalloids and red cells is the first priority, followed by blood component therapy as indicated by the haematocrit, coagulation tests, platelet count and clinical features. Serial monitoring of the response to treatment is essential. Oxytocin and prostaglandin will correct uterine atony, and appropriate surgical intervention is required for traumatic bleeding. Ligation of the uterine arteries, ovarian arteries and internal iliac arteries will usually control uterine bleeding, arterial embolization also being effective. Hysterectomy should be considered as well. Catastrophic bleeding may also arise in complications such as rupture of the liver and acute fatty liver of pregnancy. These rare complications are best managed by a multidisciplinary team involving the obstetrician, anaesthetist, haematologist, hepatologist and renal physician. The rupture of aneurysms in the splenic artery and in other branches of the aorta can result in massive haemorrhage during pregnancy and following delivery.

Nitric oxide in the uteroplacental, fetoplacental, and peripheral circulations in preeclampsia.

OBJECTIVE: Altered production of nitric oxide by the vascular endothelium may influence the pathogenesis of preeclampsia. The aim of this study was to measure circulating levels of nitric oxide metabolites (nitrites) in the uteroplacental, fetoplacental, and peripheral circulation of preeclamptic pregnancies compared with normotensive controls. METHODS: Fifteen women with preeclampsia were compared with 16 women with normotensive pregnancies. At cesarean, blood samples were taken from the uterine vein draining the placental site, the umbilical vein, and the antecubital vein after delivery of the baby but before delivery of the placenta. Plasma nitrites were measured using the Greiss reaction after conversion of plasma nitrates to nitrites using nitrate reductase. RESULTS: Nitric oxide metabolites were higher in the uteroplacental (P < .01), fetoplacental (P < .001), and peripheral (P < .02) circulations in samples from preeclamptic pregnancies compared with control pregnancies. In samples from the fetoplacental circulation only, nitric oxide metabolite levels were negatively correlated with gestational age (r = -.489, P < .01) and birth weight (r = -.544, P < .004). Nitric oxide metabolite levels were not significantly correlated with blood pressure, placental weight, or maternal age. CONCLUSION: In established preeclampsia, production of nitric oxide was higher in the uteroplacental, fetoplacental, and peripheral circulation than in normotensive pregnancies. This increase may be part of a compensatory mechanism to offset the pathologic effects of preeclampsia.

Personal hormone monitoring for contraception.

OBJECTIVE: To determine the effectiveness and acceptability of personal hormone monitoring for contraception. DESIGN: A large prospective study was carried out on personal hormone monitoring for contraception when used with abstinence during the identified fertile days. SETTING: Three country study under the auspices of the departments of Obstetrics and Gynaecology of the Universities of Birmingham, Dublin and Dusseldorf SUBJECTS: Seven hundred and ten women, median age 30, were recruited from the general population. They were required to have regular menstrual cycles (23-35 days) and to be delaying their next pregnancy. INTERVENTIONS: Personal hormone monitoring consists of a hand held monitor and disposable test sticks which measure changes in urinary concentrations of oestrone-3-glucuronide and luteinising hormone. An algorithm estimated the fertile days which were displayed by a red light. OUTCOME MEASURES AND RESULTS: One hundred and sixty two pregnancies occurred in 7209 cycles of use, of which 67 were method related pregnancies. The 13 cycle life-table method pregnancy rate (95 per cent CI) was 12. 1 per cent (9.3-14.8). The system allowed analysis of the effect of changes to the algorithm to modify the defined fertile period. As a result the algorithm was changed to increase the median warning of the luteinising hormone surge to six days. With the revised algorithm, half of the method pregnancies would have been prevented giving a calculated method pregnancy rate of 6.2 per cent (4.2-8.3) and method efficacy of 93.8 per cent. The continuation rate after 13 cycles was 78 per cent. CONCLUSION: Personal hormone monitoring proved simple to use and will be of value to women who do not want to use other methods of contraception.

PIP: A newly developed personal system of hormone monitoring allows the rapid assay of estrone-3-glucuronide (EG) and luteinizing hormone (LH) in urine to determine the fertile period. The Persona system consists of disposable test sticks to measure EG and LH concentrations in early morning urine and a hand-held monitor that indicates by the use of red and green lights the fertile and infertile phases of the cycle. The monitor stores information for the previous 6 cycles and adapts to the individual user's patterns. The effectiveness of this regimen when used with abstinence during the identified fertile period was investigated in a prospective population-based study conducted in the UK, Ireland, and Germany. 710 women (median age, 30 years) with regular menstrual cycles were enrolled. The continuation rate after 13 cycles was 78%. 162 pregnancies occurred in 7209 cycles of use, 67 of which were method-related. The 13-cycle life-table method pregnancy rate was 12.1% (95% confidence interval (CI), 9.3-14.8%). As a result of these findings, the algorithm was changed to increase the median warning of the LH surge from 4 to 6 days. Had this revised algorithm been used, the method pregnancy rate would have been reduced to 6.2% (95% CI, 4.2-8.3%) and method efficacy increased to 93.8%. The total efficacy rate compares favorably with pregnancy rates in women using other nonhormonal methods of fertility control. Women with cycle lengths of 23-35 days can expect to be required to abstain from intercourse for 6-12 days each cycle.

Uteroplacental hemostasis in intrauterine fetal growth retardation.

During pregnancy, extensive hemostatic changes occur in the uteroplacental circulation. Invading endovascular trophoblast cells induce physiological adaptations of uterine spiral arteries, required to accommodate the increased maternal blood flow to the intervillous space of the placenta as pregnancy advances. Much of the vascular endothelium and the underlying medial smooth muscle is replaced by trophoblasts, and fibrin or fibrinoid forms a major morphological feature of the arterial walls. Compared with endothelial cells, the trophoblast lining decidual spiral arteries have a reduced capacity to lyse fibrin, and recent studies have shown this to be caused by high levels of plasminogen activator inhibitors (PAI-1 and PAI-2). In pregnancies complicated by intrauterine fetal growth retardation (IUGR), with or without superimposed preeclampsia, a restricted physiological adaptation of uteroplacental spiral arteries is coupled with vascular lesions containing increased fibrin deposition. Significantly higher levels of PAI-1 are found in blood from the uterine vein at delivery and in tissue extracts of the placenta in these pregnancies than are found in normal pregnancy. Recent tissue culture studies have provided new information on the role of trophoblast cells in maintaining hemostatic control in the uteroplacental circulation in pregnancy. Cytotrophoblast cells isolated from the placenta and placental bed from IUGR pregnancies express significantly higher levels of PAI-1, coupled with a significant decrease in plasminogen activator activity, compared with trophoblast cells from normal pregnancy maintained in culture. This localized increased production of PAI-1 may play an important part in restricting endovascular trophoblast invasion in early pregnancy and increasing fibrin deposition and reducing uteroplacental blood flow in pregnancies complicated by IUGR.

Perinatal aspects of inherited thrombophilia.

The identified main causes of inherited thrombophilia are deficiencies of antithrombin, protein C and protein S, activated protein C (APC) resistance and the factor V Leiden mutation, mutant factor II, and inherited hyperhomocysteinemia. In women from symptomatic families these defects may be associated with an increased risk of venous thrombosis in pregnancy and recurrent fetal loss. Inherited thrombophilia is common and appears to be a multigene disorder. The thrombotic risk would seem to be greatest in women with antithrombin deficiency and more than one thrombophilia defect. The abnormalities that are now recognized represent only part of the genetic predisposition to thrombosis. In assessing thrombotic risk in pregnancy, acquired risk factors as well as genetic predisposition should be considered. Increasing age, obesity, immobility, and delivery by cesarean section are major risk factors. Pregnancy should be planned, and each patient should be managed on an individual basis. In pregnancy, heparin is the anticoagulant of choice, and as far as possible, treatment with warfarin should be avoided because of the risks to the fetus. When patients are on long-term treatment with warfarin, pregnancy should be avoided, and warfarin should be discontinued prior to embarking on a pregnancy or as soon as pregnancy is suspected and before 6 weeks' gestation. In women from symptomatic families with antithrombin deficiency, adjusted dose heparin throughout pregnancy is recommended and warfarin for at least 3 months post partum. In protein C and protein S deficiency, factor V Leiden, or mutant factor II, treatment can be based on personal and family history. Thromboprophylaxis in late pregnancy and post partum should be considered. Fetal loss may be increased in women with inherited thrombophilia. The risk appears greatest in women with antithrombin deficiency and women with more than one thrombophilia defect. A number of reports have claimed that prophylactic treatment with heparin during pregnancy has resulted in successful pregnancy in women with recurrent fetal death and inherited thrombophilia.

Plasminogen activators and inhibitors in ovarian adenocarcinomas.

The fibrinolytic process was examined in cultures from malignant epithelial ovarian tumors and compared to normal ovarian tissue. The fibrinolytic enzymes, urokinase plasminogen activator (uPA) antigen and activity, tissue plasminogen activator (tPA) antigen and activity, plasminogen activator inhibitor 1 (PAI-1) and plasminogen activator inhibitor 2 (PAI-2) antigen were measured in short-term primary cultures at weekly intervals over a 3-week period. The cultures comprised of 15 ovarian adenocarcinomas and 12 normal ovarian tissue samples. The concentration of uPA antigen (p < 0.01) and activity (p < 0.01) and (p < 0.05) levels were higher in malignant specimens on all 3 count days. Activity levels of tPA were elevated significantly in malignant specimens on days 7 and 21 (p < 0.05). No significant difference was found between PAI-1 levels. PAI-2 antigen levels were significantly higher in the tumor specimens on days 14 and 21 (P < 0.01). These data indicate that uPA may have a significant role in the biology of ovarian cancer and may be an important factor in early tumor spread. Further work is required on the effects of intervention in this biological process.

Inherited thrombophilia and pregnancy: the obstetric perspective.

The identified main causes of inherited thrombophilia are deficiencies of antithrombin (AT), protein C, or protein S, resistance to activated protein C associated with Factor V Leiden mutation, mutant factor II, and inherited hyperhomocysteinemia. For women from symptomatic families, these defects may be associated with an increased risk of venous thrombosis during pregnancy and/or recurrent fetal loss. Inherited thrombophilia is common and appears to be a multigenic disorder. The thrombotic risk seems to be greatest for women who have AT deficiency or more than one thrombophilic defect. The abnormalities that are now recognized are only part of the genetic predisposition to thrombosis. When assessing thrombotic risk during pregnancy, acquired risk factors as well as genetic predisposition should be considered. Increasing age, obesity, immobility, and delivery by cesarean section are major acquired risk factors. Pregnancy should be planned as far as possible, and each patient should be managed individually. During pregnancy, heparin is the anticoagulant of choice, and treatment with warfarin should be avoided because of risks for the fetus. When patients receive long-term treatment with warfarin, pregnancy should be avoided or planned, and warfarin should be discontinued before conception or as soon as pregnancy is confirmed and before 6-weeks' gestation. For women who have AT deficiency, the incidence of thrombosis during pregnancy is between 20 and 40%. Adjusted-dose heparin throughout pregnancy is recommended, followed by warfarin for at least 3 months postpartum. For patients who have Factor V Leiden, mutant factor II, or a deficiency of protein C or protein S, treatment can be based on personal and family history. Thromboprophylaxis during late pregnancy and postpartum should be considered. Fetal loss may be increased for women with inherited thrombophilia. The risk appears to be greatest for women with AT deficiency and women with more than one thrombophilic defect. For women with recurrent fetal death and inherited thrombophilia, a number of case reports claim that prophylaxis with heparin during pregnancy has resulted in successful pregnancy.

Hemostasis in the uteroplacental and peripheral circulations in normotensive and pre-eclamptic pregnancies.

OBJECTIVE: Our purpose was to determine the hemostatic changes in the uteroplacental and peripheral circulations in normotensive and pre-eclamptic pregnancies. STUDY DESIGN: This prospective, observational study involved 2 patient groups. Group 1 consisted of 30 normotensive women and 22 women with pre-eclampsia who were followed up longitudinally through pregnancy and post partum. Group 2 consisted of 20 women with established pre-eclampsia and 19 normotensive control subjects, all undergoing cesarean section. Plasma levels of thrombin-antithrombin III complex, soluble fibrin, plasmin-alpha2-antiplasmin complex, and fibrin-degradation product (D-dimer) were measured in blood drawn from the antecubital vein (group 1) and from both the antecubital and uterine veins (group 2). Data were analyzed by analysis of variance. RESULTS: In group 1 levels of thrombin-antithrombin III complex, soluble fibrin, and fibrin-degradation product were significantly higher during normal pregnancy than at 6 weeks post partum. Plasmin-alpha2-antiplasmin complex levels did not change. No differences between the pre-eclamptic and normotensive pregnancy groups were found for any of the hemostatic markers. In group 2 normotensive women undergoing cesarean section, thrombin-antithrombin III complex and soluble fibrin levels were significantly higher in the uterine vein than in the antecubital vein. In group 2 women with pre-eclampsia, thrombin-antithrombin III complex and fibrin-degradation product levels were significantly higher in the uterine vein than in the antecubital vein. In addition, plasmin-alpha2-antiplasmin complex and fibrin-degradation product levels were higher and soluble fibrin levels were lower in the uterine vein in the pre-eclamptic group than in the normotensive group. CONCLUSION: Both the coagulation and fibrinolytic systems are activated during normal pregnancy. Activation of these systems is more marked in the uteroplacental circulation than in the systemic circulation in both normotensive and pre-eclamptic pregnancies. An abnormal pattern of hemostasis occurs in the uteroplacental circulation in pre-eclampsia.