Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin. Can low molecular weight heparin replace unfractionated heparin during peripheral arterial reconstruction? An open label prospective randomized controlled trial. A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia. A matched study to determine whether low-dose aspirin without heparin improves pregnancy rates following frozen embryo transfer and/or affects endometrial sonographic parameters. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies) Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin. Low-dose aspirin therapy to prevent preeclampsia. A study of use of low dose aspirin in prevention of pregnancy induced hypertension. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. Low dose aspirin in prevention of pregnancy-induced hypertension in primigravidae at the Muhimbili Medical Center, Dar es Salaam.
To compare the 2 most efficacious therapeutic regimens, intravenous immunoglobulin (IVIG) and anticoagulation with low molecular weight (LMW) heparin plus low-dose aspirin, in women with recurrent pregnancy loss associated with antiphospholipid antibodies (aPL).
                We examined 40 women with recurrent abortion (at least 3 occurrences) and repeatedly positive test results for anticardiolipin or lupus anticoagulant. The subjects were randomly assigned to treatment with IVIG or LMW heparin plus low-dose aspirin. Both therapies were started when the women were pregnant as documented by a positive urine test. IVIG was stopped at the thirty-first week of gestation, aspirin at the thirty-fourth week, and heparin at the thirty-seventh week. The primary outcome of interest was the rate of live births with the 2 treatments.
                The characteristics of the 2 groups were similar at the time of randomization. The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births (84%) than those treated with IVIG (57%).
                Treatment with LMW heparin plus low-dose aspirin should be considered as the standard therapy for recurrent pregnancy loss due to aPL. To compare the efficacy of low-dose aspirin alone versus low-dose aspirin plus low molecular weight heparin in pregnant women with antiphospholipid syndrome and recurrent miscarriage as prophylaxis against pregnancy loss.
                From a regional miscarriage clinic, 119 consecutive women with persistently positive tests for lupus anticoagulant and/or anticardiolipin immunoglobulin G and M antibody were invited to participate in a randomized, controlled trial between 1997 and 2000. After ethical approval and adherence to a written protocol, 12 women were unwilling to participate, five failed exclusion/inclusion criteria, and four were nonpregnant. Laboratory analysis was performed by Sheffield University Coagulation Department, electronically generated randomization by Manchester University Centre for Cancer Epidemiology, and data collection and analysis by a research officer at Leeds University. Viability ultrasound every 2 weeks was provided until 12 weeks' gestation before transfer to the pregnancy support antenatal clinic.
                Ninety-eight women were randomized before 12 weeks' gestation. Forty-seven received low-dose aspirin 75 mg daily (group A), and 51 received low-dose aspirin plus low molecular weight heparin 5000 U subcutaneously daily (group B) throughout pregnancy. There were 13 pregnancy losses and 34 live births in group A and 11 losses and 40 live births in group B. The live-birth rate was 72% in group A and 78% in group B (odds ratio 1.39, 95% confidence interval 0.55, 3.47). There were no cases of maternal thrombosis in either group.
                A high success rate is achieved when low-dose aspirin is used for antiphospholipid syndrome in pregnancy. The addition of low molecular weight heparin does not significantly improve pregnancy outcome. The purpose of this study was to compare the use of low-dose aspirin alone with heparin and low-dose aspirin in the treatment of the antiphospholipid antibody syndrome.
                A prospective, single-center trial included 50 patients who were alternately assigned to treatment. Each patient had at least three consecutive spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared by chi(2) analysis and Fisher's exact test.
                Viable infants were delivered of 11 of 25 (44%) women treated with aspirin and 20 of 25 (80%) women treated with heparin and aspirin (p < 0.05). There were no significant differences between the low-dose aspirin and the heparin plus low-dose aspirin groups with respect to gestational age at delivery (37.8 +/- 2.1 vs 37.2 +/- 3.4 weeks), number of cesarean sections (18% vs 20%), or complications.
                Heparin plus low-dose aspirin provides a significantly better pregnancy outcome than low-dose aspirin alone does for antiphospholipid antibody-associated recurrent pregnancy loss. This study was conducted to determine if lower dose heparin (LD Heparin) combined with aspirin is as efficacious as higher dose heparin (HD Heparin) for the treatment of the antiphospholipid antibody syndrome in women seeking pregnancy. The method of the study was a prospective, single center trial including 50 patients who were consecutively assigned to treatment. Each patient had at least three consecutive, spontaneous pregnancy losses, positive antiphospholipid antibodies on two occasions, and a complete evaluation. Data were compared using Fisher's exact test. Viable infants were delivered from 20/25 (80%) women treated with higher dose heparin vs. 19/25 (76%) of women treated with lower dose heparin. There were no significant differences between groups with respect to gestational age at the time of delivery (37.2 +/- 3.4 versus 37.7 +/- 1.6 weeks), maternal complications, or fetal complications. A lower dose of heparin plus aspirin was as effective as higher dose heparin for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss. This study was undertaken to evaluate the effect of low molecular weight heparin (LMWH) compared with unfractionated heparin (UFH) on the rate of occlusion and bleeding during peripheral vascular surgery.
                The study was an open label, prospective, randomized trial, carried out by 20 Swedish surgical and vascular surgical departments that report to the Swedish Vascular Registry (SWEDVASC). Study subjects included patients undergoing peripheral vascular procedures, except carotid surgery. Of the 849 patients included, 817 were followed up to 30 days. LMWH (40 mg of enoxaparin) or UFH (5000 IU heparin) was given intravenously immediately before clamping. The same formulation in diluted form was used for vascular rinsing. Main outcome measures included patent reconstruction at day 1, perioperative blood loss, and the percentage of patients requiring protamin. Further, 30-day data for mortality, repeat operation, and recurrent occlusion are reported.
                The mortality rate at 30 days was 2.7%, with no difference between groups. The patency rate at 1 day was 91.2% to 98.4%, depending on diagnosis and type of reconstruction. No difference was recorded between study groups (0.6 < P < 1.0). At 30 days the patency rate was 83.1% to 100% (0.2 < P <.9). Median blood loss was 350 mL (interquartile range [IQR], 200-800 mL) in the LMWH group and 425 mL (IQR, 200-900 mL) in the UFH group (P =.02). Protamin was given to significantly fewer patients in the LMWH group (P =.001). LMWH was comparable to UFH during peripheral vascular reconstruction in terms of 1-day and 30-day graft patency, operative blood loss, and hemorrhagic complications. Protamine was required less often after LMWH. In this randomized trial LMWH was as effective as UFH in preventing thrombosis without excess bleeding or hemorrhagic complications. To determine if aspirin (ASA) therapy reduces the incidence of pre-eclampsia in women at high risk of this condition.
                Randomised clinical trial. We recruited pregnant women with gestational age at randomisation <14 weeks, who satisfied the following criteria: chronic hypertension, history of severe pre-eclampsia or eclampsia or intrauterine growth retardation (IUGR) or intrauterine foetal death. Nineteen women in the no-treatment group and 16 in the ASA group were successfully followed up.
                The mean birthweight was higher in the ASA group than in the no-treatment group (2790 g (S.D. 340 g) versus 2616 g (S.D. 779 g)), but the difference was not statistically significant. We found no statistically significant differences between the groups in the proportion of infants with birthweight below 2500 g (13.3% versus 29.4%) and the number of cases with pregnancy-induced hypertension (PIH)/pre-eclampsia (31.3% versus 36.8%).
                These limited data give some support to the potential favourable effect of early treatment with ASA in pregnant women at risk of PIH and IUGR. The objective of the matched, controlled study was to determine whether low-dose aspirin therapy without heparin improves pregnancy rates following frozen embryo transfer.
                Thirty-six women who did not achieve a pregnancy following fresh embryo transfer and who had frozen embryos available for another transfer were included. Eighteen women were treated with 81 mg aspirin from day 2 of the cycle through pregnancy testing. If the beta-human chorionic gonadotropin level was positive, aspirin was continued through the pregnancy. Eighteen women were not given aspirin. The mean outcome variables were pregnancy and implantation rates.
                The clinical pregnancy rate in the aspirin group was 11.1%, compared with 33.3% for the controls, and implantation rates were 2.9 and 10.9%, respectively.
                No positive effects of low-dose aspirin therapy on pregnancy rates following frozen embryo transfer were observed. To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies).
                Randomised controlled trial.
                Specialist clinic for recurrent miscarriages.
                90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies.
                Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks' gestation.
                Rate of live births with the two treatments.
                There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%).
                Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone. 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. Our aim was to test the hypothesis that acetylsalicylate (aspirin) treatment reduces the incidence or severity of pregnancy-associated hypertension.
                Patients were nulliparous, healthy, and with a singleton gestation at between 20 and 22 weeks' gestation. A sample size of 600 patients was calculated on the basis of p < or = 0.05 and 90% power of observation. A 2-week placebo-controlled "run-in" was used to select compliant patients. Randomization occurred at 24 weeks, with 60 mg of aspirin or placebo treatment from randomization to delivery.
                Follow-up was maintained on 99% of the patients. The randomized patients had a 94% pill compliance index. At randomization, serum thromboxane medians were similar in both groups. Thromboxane B2 levels in the aspirin group decreased significantly from baseline at 29 to 31 weeks, 34 to 36 weeks, and at delivery as compared with an overall increase in the placebo group. Preeclampsia developed in five of 302 women (1.7%) who received aspirin versus 17 of 302 (5.6%) who received the placebo (p = 0.009). Preeclampsia was severe in one aspirin and in six placebo recipients (p = 0.06).
                Daily ingestion of 60 mg of aspirin beginning at 24 weeks' gestation significantly reduced the occurrence of preeclampsia. Forty-six nulliparous women in third trimester of pregnancy with a raised blood pressure of 30 mm Hg (systolic) or/and 15 mm Hg (diastolic) or both, over baseline values were treated with 75 mg of aspirin per day. The results are compared with another 48 age, height, weight, and gestational period matched nulliparaous women with similar condition for trial selection, who were treated as control. There is considerable more number of cases in the control group than in aspirin treated group showing subsequent rise of BP, appearance of proteinuria, and severe pre-eclamptic toxaemia. The aspirin treated group showed increased mean gestational age at termination 39.4 +/- 2.6 weeks as against 38.2 +/- 3.4, increased foetal weight 2860 +/- 552 g as against 2540 +/- 720 g. No case of neonatal haemorrhagic manifestations or congenital malformations were seen. However not much result is obtained with aspirin therapy in cases with established pregnancy induced hypertension or with proteinuria. Hence it is concluded that aspirin therapy should be given to prevent pregnancy induced hypertension. As predictability of other screening tests are not unequivocal, criterion used in this series for screening may be used. Antithrombotic therapy with heparin plus aspirin reduces the rate of ischemic events in patients with unstable coronary artery disease. Low-molecular-weight heparin has a more predictable anticoagulant effect than standard unfractionated heparin, is easier to administer, and does not require monitoring.
                In a double-blind, placebo-controlled study, we randomly assigned 3171 patients with angina at rest or non-Q-wave myocardial infarction to receive either 1 mg of enoxaparin (low-molecular-weight heparin) per kilogram of body weight, administered subcutaneously twice daily, or continuous intravenous unfractionated heparin. Therapy was continued for a minimum of 48 hours to a maximum of 8 days, and we collected data on important coronary end points over a period of 30 days.
                At 14 days the risk of death, myocardial infarction, or recurrent angina was significantly lower in the patients assigned to enoxaparin than in those assigned to unfractionated heparin (16.6 percent vs. 19.8 percent, P=0.019). At 30 days, the risk of this composite end point remained significantly lower in the enoxaparin group (19.8 percent vs. 23.3 percent, P=0.016). The need for revascularization procedures at 30 days was also significantly less frequent in the patients assigned to enoxaparin (27.1 percent vs. 32.2 percent, P=0.001). The 30-day incidence of major bleeding complications was 6.5 percent in the enoxaparin group and 7.0 percent in the unfractionated-heparin group, but the incidence of bleeding overall was significantly higher in the enoxaparin group (18.4 percent vs. 14.2 percent, P=0.001), primarily because of ecchymoses at injection sites.
                Antithrombotic therapy with enoxaparin plus aspirin was more effective than unfractionated heparin plus aspirin in reducing the incidence of ischemic events in patients with unstable angina or non-Q-wave myocardial infarction in the early phase. This benefit of enoxaparin was achieved with an increase in minor but not in major bleeding. There is evidence that aspirin in low doses favourably influences the course and outcome of pregnancy in women at risk of developing pregnancy-induced hypertension. We conducted a double blind prospective randomized study to investigate the effect of low dose aspirin in preventing pregnancy-induced hypertension. Two hundred and one primigravidae from twenty weeks of pregnancy and above were screened using the roll-over test. Of the 127 women with an increase in blood pressure during the roll-over test, 126 women entered the study and were treated with a daily dose of either aspirin (80 mg) or placebo up to 10 days before the expected date of delivery. Samples of urine were collected for detection of aspirin. The incidence of pregnancy-induced hypertension in the aspirin treated group was significantly lower than in the placebo treated group; 3.17% versus 15.9% with a p value of 0.02. It is concluded that low daily doses of aspirin taken from twenty weeks of pregnancy significantly reduce the incidence of pregnancy-induced hypertension, possibly through the correction of an imbalance in levels of thromboxane and prostacyclin.
Combined unfractionated heparin and aspirin may reduce pregnancy loss by 54%. Large, randomised controlled trials with adequate allocation concealment are needed to explore potential differences between unfractionated heparin and LMWH.
[Note: The 15 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]