Lack of anti-factor Xa activity in umbilical cord vein samples after subcutaneous administration of heparin or low molecular mass heparin in pregnant women. A randomised double-blind placebo controlled trial of low molecular weight heparin as prophylaxis in preventing venous thrombolic events after caesarean section: a pilot study. Prevention of postpartum venous thrombosis with low doses of heparin. Thromboprophylaxis following caesarean section--a comparison of the antithrombotic properties of three low molecular weight heparins--dalteparin, enoxaparin and tinzaparin. Bone density changes in women who receive thromboprophylaxis in pregnancy. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. The rheological changes after cesarean section: The influence of low molecular weight or unfractionated heparin on the rheological properties of blood. [Prevention of thromboembolism with low molecular weight heparin (Fragmin) in obstetrics]. [Thrombo-embolytic prophylaxis using physiotherapy with and without low doses of heparin in gynecology and obstetrics. Results of a controlled and randomized mult-cancer study]. Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin. Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin. The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial.
Prophylaxis of thromboembolism with low molecular mass (LMM) heparin may offer several advantages over conventional heparin during pregnancy. Heparin-related side effects as osteoporosis, local allergy, thrombocytopenia and increase in liver enzymes may occur less frequently with LMM heparin. However, LMM heparins of different origins have to be considered as individual pharmaceutical compounds. This is of special clinical importance regarding a possible placental passage. We performed a randomized controlled study comparing the anti-factor Xa activities in plasma samples of 60 pregnant women undergoing delivery at term and in the umbilical cord vein of the newborn after subcutaneous administration of 5,000 IU unfractionated (UF) heparin or 1,500 activated partial thromboplastin time units LMM heparin or placebo. Injections were performed about 2 h prior to the delivery. Maternal and fetal blood samples were taken at the same time to assay heparin activity by the heptest coagulation assay and the S2222 chromogenic substrate method. LMM heparin was detected in all maternal plasma samples whereas UF heparin was measurable only in about one third of them. UF heparin as well as LMM heparin were not detectable in samples taken from the umbilical cord vein. The data demonstrate that neither UF nor the LMM heparin used in this study cross the placenta in relevant inhibitory activity towards factor Xa. This finding is in accordance with the previous experiences regarding the safe administration of other LMM heparins for prophylaxis of thromboembolism during pregnancy. To pilot a protocol for a national multicentre randomised trial in which a low molecular weight heparin will be compared with placebo for prevention of venous thrombotic events occurring within six weeks after caesarean section.
                Double-blind randomised controlled trial.
                Tertiary care centre.
                Seventy-six women having had a caesarean section, 37 in the control group and 39 in the Dalteparin group.
                Consenting patients having had an emergency or elective caesarean section were commenced on study medication 6-24 hours post-operatively. The study medication, dalteparin 2,500 iu or saline, was given subcutaneously once daily for four or five days post-operatively depending on the patient's length of stay. Patients were reviewed in hospital for operative outcomes and contacted at two and six weeks post-operatively.
                Of the 141 women given information about the trial, 76 (54%) consented to participate. Follow up to six weeks was achieved in all women who were recruited. More women in the placebo arm had general anaesthesia, but otherwise the two groups had similar characteristics at randomisation. There was only one occurrence of a deep vein thrombosis during the study. This patient was in the treatment arm and the thrombosis occurred between two and six weeks post-operatively. All other outcomes were similar in the two groups.
                Our experience of a 26% recruitment rate, the thrombosis rate of 1.3% (95% CI 0.03-7.1%) and the contactability of all participants two and six weeks post-operatively, indicates that this study is feasible. Postpartum superficial and deep venous thrombosis were found in 22.3% and 5.3% of women with varicose veins who delivered vaginally, or by cesarean section. The preventive use of low doses of heparin (5,000 U every 12 h injected subcutaneously) in 116 parturients with varicose veins reduced significantly the incidence of postpartum venous thrombosis. None of the 26 women with previous thrombosis who received preventive treatment, developed such an event. Pharmacological thromboprophylaxis is increasingly being used after caesarean section to prevent venous thromboembolism. Although a variety of low molecular weight heparins (LMWH) have been used no comparative study exists on their effects on the haemostatic system in this situation. Furthermore, their antithrombotic effect may be mediated through effects other than their inhibitory effect on activated factor X. We compared the plasma anti-factor Xa activity, plasma concentration of tissue factor pathway inhibitor (TFPI) and the reduction in plasma thrombin-antithrombin (TAT) complex concentration in 30 women randomised to receive either dalteparin 5,000 IU anti-Xa once daily (n = 10), enoxaparin 4,000 IU anti-Xa once daily (n = 10) or tinzaparin 50 IU/kg anti-Xa (average dose 3,650 anti-Xa units) once daily (n = 10) following caesarean section. Sampling occurred at 0, 1, 3, 6, 12 and 24 h relative to time of dosing. All preparations produced an increase in mean anti-Xa assay (p < 0.0001), a reduction in mean TAT (p < 0.05) and an increase in mean TFPI concentration (p <0.05). Analysis of variance (ANOVA) revealed a significant difference between the LMWHs in terms of mean anti-factor Xa activity (p < 0.005) and reduction in plasma TAT concentration (p < 0.005). Post hoc analysis indicated that the anti-Xa values of the groups receiving enoxaparin and dalteparin were significantly higher than those of the group receiving tinzaparin (p < 0.05), but not significantly different from each other. Post hoc analysis of the reduction in plasma TAT concentration showed the reduction to be significantly less in the group receiving enoxaparin compared to the dalteparin and tinzaparin groups (p < 0.05), which did not differ significantly from each other. There was no significant difference between treatment groups with regard to plasma concentration of TFPI. These findings demonstrate that LMWHs differ in their effects on haemostatic parameters including thrombin generation as assessed by TAT. The increase in TFPI may be an additional mediator of LMWH's antithrombotic effects. Although these findings demonstrate that LMWHs differ in their haemostatic effects, this does not necessarily infer a clinical difference between these agents. The purpose of this study was to compare unfractionated heparin therapy to the low molecular weight heparin, enoxaparin sodium, and their effects on bone mineral density over the course of pregnancy.
                Pregnant patients whose condition required thromboprophylaxis were recruited in this prospective randomized controlled trial and were assigned to receive either unfractionated heparin therapy or low molecular weight heparin therapy. Bone mineral density was measured by dual energy x-ray absorptiometry at the proximal femur on enrollment and again shortly after delivery.
                One hundred twenty women were enrolled, and 98 women completed the study. There was no difference in the change in bone mineral density at the femoral neck (P = .054) or total proximal femur (P = .584) between groups. Only 1 of 40 patients (2.5%) who received unfractionated heparin therapy and 1 of 49 patients (2.0%) who received low molecular weight heparin therapy (P = 1.0) experienced bone loss of > or = 10% at the femoral neck.
                In this study, the incidence of clinically significant bone loss (> or = 10%) in the femur in women who received thromboprophylaxis in pregnancy is approximately 2% to 2.5% and appears to be similar, regardless of whether the patient receives low molecular weight heparin therapy or unfractionated heparin therapy. Venous thromboembolism remains an important cause of maternal mortality. For women at risk during pregnancy, the recommended venous thromboembolismprophylaxis is unfractionated heparin. Low molecular weight heparins, such as dalteparin, also may be suitable, but randomised trials have not been performed. Pregnant women (105) with confirmed previous or current thromboembolism were randomised to receive either unfractionated heparin twice daily (mean 20569 IU/day) or dalteparin once daily (mean 4631 IU anti-factor Xa units/day) subcutaneously for thromboprophylaxis during pregnancy and postpartum period. Recurrence of venous thromboembolism and safety of treatments were assessed. Dalteparin administered once daily was safe and effective in thromboprophylaxis during pregnancy and postpartum. Thromboembolic complications remain an important cause of maternal mortality. The present recommendations favour for prophylaxis unfractionated (UFH) and low molecular weight heparin (LMWH). We investigated 150 pregnant women before and after cesarean section in three randomized groups. Fifty women received no prophylaxis (group I), 50 women UFH two times 5000 IU/day (group III) and 50 women Dalteparin 5000 U/day (group II). We determined the blood count, the rheological parameters and cholesterol, triglycerides, D-dimer, fibrinogen and the anti-Xa-level. We found a classical hemodilution, with increase of erythrocyte aggregation and plasma viscosity postoperatively. The fibrinogen turnover and D-dimer concentration were elevated. The patients with Dalteparin prophylaxis showed lower thrombin activation, minor changes in the cholesterol and triglycerides level and an improvement of red cell deformability in low shear regions. Our results demonstrated an influence of Dalteparin on the rheological parameters post surgery. The DVT incidence was 1.33% generally and occurred only in the Control group and in women with unfractionated heparin. We observed no side effects such as major bleeding, osteopenia or allergy. A total of 130 obstetrical patients were treated with either low molecular weight (LMW) or unfractionated (UFH) heparin as part of prospective study comparing their efficacy in the prevention of thromboembolism. A single daily dose of 2500-5000 anti-Xa-units LMW heparin (Fragmin) or two to three daily doses of 5000 IU UFH (Liquemin) were given to two groups of 15 patients with therapeutic tocolysis and 50 patients with cesarean section. Patients with cesarean section were given 500 ml Dextran 60 i.v. during surgery followed by subcutaneous injection of heparin eight to ten hours after surgery. Heparin therapy was continued for ten days after surgery. None of the patients exhibited clinical signs of thrombosis. The majority of patients showed symptoms of local irritation at the site of heparin injection (69% of patients with LMW heparin; 80% of patients with UFH). Hematomas at the site of injection were significantly smaller when LMW heparin was used instead of UFH. A number of patients experienced headache after heparin application (10% of patients with LMW heparin; 13% of patients with UFH). There were no cases of post surgical haemorrhage. Comparison of daily profiles revealed a significantly higher anti-Xa-activity of LMW heparin compared to UFH. In contrast, other coagulation parameters were not different in the two experimental groups (antithrombin III, partial thrombin time, thrombin time). Hematologic parameters and liver enzymes were in the physiological range in both experimental groups and none of the patients exhibited signs of heparin induced thrombocytopenia.(ABSTRACT TRUNCATED AT 250 WORDS) nan The purpose of this study was to conduct pilot studies for large randomized controlled trials to compare low-molecular-weight heparin with placebo for antenatal thromboprophylaxis (trial 1), and for thromboprophylaxis after cesarean delivery (trial 2).
                Multicenter randomized controlled trials (trial 1, 23 units; trial 2, 8 units) were conducted. Pregnant women at increased risk for thromboembolic disease were eligible for trial 1; women who underwent cesarean delivery were eligible for trial 2. The interventions were once daily injections of low-molecular-weight heparin or placebo. Primary outcomes were as follows: trial 1, confirmed symptomatic thromboembolic events and symptomatic osteoporotic fractures; trial 2, confirmed symptomatic thromboembolic events and wound complications.
                Sixteen women were recruited for trial 1; 1 woman in the placebo group had a symptomatic thromboembolic event. One hundred forty-one women were recruited for trial 2; 1 woman in the low molecular weight heparin group had a symptomatic thromboembolic event.
                Poor recruitment indicates that large-scale trials using these designs would be difficult. Collection of data on the number of women that are eligible and the reasons for nonrecruitment in future trials of these interventions would allow a better understanding of the reasons for poor recruitment. Low molecular weight heparins are used extensively for thromboprophylaxis. The aim of this study was to compare the activity of the low molecular weight heparin, enoxaparin, 20 mg and 40 mg, given once per day with unfractionated heparin, 7500iu given twice per day, in terms of their anti-Xa activity in puerperal women following caesarean section and with an additional risk factor for venous thromboembolism. Seventeen women were randomised to receive one of the three treatments. The anti-Xa activity associated with each treatment was measured prior to treatment and at 2, 4, 6, 12 and 24 hours. The mean anti-Xa values of the groups receiving enoxaparin, 20 mg and 40 mg, were significantly higher than those of the group receiving unfractionated heparin. There was no difference between the two enoxaparin groups in terms of the anti-Xa activity profiles. This study suggests that the use of enoxaparin is superior to unfractionated heparin in terms of anti-Xa activity. The risks of long-term antenatal subcutaneous heparin therapy were assessed in a small controlled trial of prophylaxis of thromboembolism. Forty patients with a documented history of previous thromboembolism were randomly allocated either to receive heparin (10000 i.u. subcutaneously twice daily) throughout pregnancy and labour or to receive no treatment (control group). All patients were treated with heparin (8000 i.u. twice daily) for 6 weeks after delivery from the first postnatal day. There appeared to be no increased risk of antenatal or postnatal bleeding associated with subcutaneous heparin, but one patient in the control group developed a deep vein thrombosis and one in the treatment group developed severe debilitating osteopenia. The withholding of epidural analgesia may have contributed to both maternal and fetal morbidity in the treatment group. There was one abortion in each group but no other fetal or neonatal losses although more babies from the treated group entered the special care baby unit. Although the numbers are too small for statistical analysis, the findings indicate that the use of long-term low-dose subcutaneous heparin is not without complications and there is need for a larger, multicentre trial to allow precise quantification of fetal and maternal risks against the risk of recurrent thromboembolism.
There is insufficient evidence on which to base recommendations for thromboprophylaxis during pregnancy and the early postnatal period. Large scale randomised trials of currently-used interventions should be conducted.