Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Incidence and prevention of deep venous thrombosis occurring late after general surgery: randomised controlled study of prolonged thromboprophylaxis. A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Antepartum treatment without early cordocentesis for standard-risk alloimmune thrombocytopenia: a randomized controlled trial. Bone density changes in women who receive thromboprophylaxis in pregnancy. Global report on preterm birth and stillbirth (3 of 7): evidence for effectiveness of interventions. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies. The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial.
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. 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. To study the incidence of late deep venous thrombosis (DVT), and to evaluate a regimen of prolonged thromboprophylaxis after general surgery.
                Randomised, controlled, open trial, with blinded evaluation.
                University hospital, Denmark.
                176 consecutive patients undergoing major elective abdominal or non-cardiac thoracic operations, of whom 118 were eligible for evaluation.
                Thromboprophylaxis with a low-molecular-weight heparin, tinzaparin, given for four weeks (n = 58), compared with one week (control group, n = 60).
                Presence of DVT established by bilateral venography four weeks after the operation.
                The incidence of late DVT in the control group was 6/60 (10%, 95% confidence interval (CI) 4% to 21%). In the prophylaxis group it was 3/58 (5.2%, 95% CI 1% to 14%) (p = 0.49).
                Prolonged thromboprophylaxis had no significant effect on the incidence of DVT occurring late after general surgery. To compare the effect of aspirin and enoxaparin on live births in women with unexplained recurrent miscarriages, as well as secondary outcomes including birth weight, uterine and umbilical blood flows, and congenital malformations.
                Multicenter randomized comparative cohort study.
                Four centers including two university hospitals, a peripheral general hospital, and a community health clinic.
                One hundred seven patients were randomized, 104 were available for analysis; 54 were randomized to enoxaparin and 50 to aspirin.
                Treatment with enoxaparin or aspirin in subsequent pregnancy.
                Subsequent live births or miscarriage, and the incidence of obstetric complications.
                Both groups had a similar live birth rate (relative risk = 0.92, 95% confidence interval: 0.58-1.46). In primary aborters, live births occurred in 17 of 18 (94%) enoxaparin-treated pregnancies compared to 18 of 22 (81%) aspirin-treated pregnancies. In the aspirin group, two pregnancies were terminated: for tricuspid insufficiency and for hemolysis, elevated liver enzymes, low platelet (HELLP) syndrome. One enoxaparin-treated infant was growth restricted (2,020 g) at 36 weeks. Preeclampsia was found in three aspirin-treated patients. Preterm delivery, placental Doppler blood flow, apgar scores, and mean birth weights were similar in both groups. In the aspirin group, one infant underwent orchidectomy after testicular torsion in utero, and one infant had hypoglycemia and convulsions.
                Both regimens were associated with a high live birth rate and few late pregnancy complications. To evaluate the effectiveness and safety of two antenatal treatment regimens designed to optimally protect fetuses against intracranial hemorrhage resulting from alloimmune thrombocytopenia while minimizing the risks associated with fetal blood sampling. The study was limited to "standard-risk" patients, who were defined as women with documented alloimmune thrombocytopenia who had not delivered an infant with an intracranial hemorrhage in a prior pregnancy.
                In this prospective multicenter study of 73 women with documented alloimmune thrombocytopenia, patients were randomized to receive either intravenous immunoglobulin (IVIG) 2 g/kg/wk (group A) or IVIG 1 g/kg/wk plus prednisone 0.5 mg/kg/d (group B), starting at approximately 20 weeks of gestation. Fetal blood sampling was performed at approximately 32 weeks of gestation, and those with fetal platelet counts less than 30,000/mL(3) were given salvage therapy.
                There were two intracranial hemorrhages; neither was due to treatment failure. The average platelet counts at the time of fetal blood sampling were 121,600/mL(3) and 116,100/mL(3), and the average birth platelet counts were 169,400/mL(3) and 134,000/mL(3) for groups A and B, respectively. Twenty-seven percent of patients in group A and 17% in group B received salvage therapy, and only one neonate in each of these subsets had a birth platelet count less than 30,000/mL(3). There were four complications after 79 fetal blood sampling procedures, leading to cesarean deliveries between 32 and 37 weeks. There was a higher incidence of gestational diabetes and a tendency to more fluid retention, mood swings, insomnia, and jitteriness in patients on prednisone and of moderate-to-severe fatigue in those on high-dose IVIG alone.
                The outcomes of both treatment groups were excellent and comparable. Early cordocentesis is not necessary when treating alloimmune thrombocytopenia in patients who have not delivered an infant with an intracranial hemorrhage in a prior pregnancy.
                ClinicalTrials.gov, www.clinicaltrials.gov, NCT00194987
                I. 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. Interventions directed toward mothers before and during pregnancy and childbirth may help reduce preterm births and stillbirths. Survival of preterm newborns may also be improved with interventions given during these times or soon after birth. This comprehensive review assesses existing interventions for low- and middle-income countries (LMICs).
                Approximately 2,000 intervention studies were systematically evaluated through December 31, 2008. They addressed preterm birth or low birth weight; stillbirth or perinatal mortality; and management of preterm newborns. Out of 82 identified interventions, 49 were relevant to LMICs and had reasonable amounts of evidence, and therefore selected for in-depth reviews. Each was classified and assessed by the quality of available evidence and its potential to treat or prevent preterm birth and stillbirth. Impacts on other maternal, fetal, newborn or child health outcomes were also considered. Assessments were based on an adaptation of the Grades of Recommendation Assessment, Development and Evaluation criteria.
                Most interventions require additional research to improve the quality of evidence. Others had little evidence of benefit and should be discontinued. The following are supported by moderate- to high-quality evidence and strongly recommended for LMICs: Two interventions prevent preterm births--smoking cessation and progesterone. Eight interventions prevent stillbirths--balanced protein energy supplementation, screening and treatment of syphilis, intermittant presumptive treatment for malaria during pregnancy, insecticide-treated mosquito nets, birth preparedness, emergency obstetric care, cesarean section for breech presentation, and elective induction for post-term delivery. Eleven interventions improve survival of preterm newborns--prophylactic steroids in preterm labor, antibiotics for PROM, vitamin K supplementation at delivery, case management of neonatal sepsis and pneumonia, delayed cord clamping, room air (vs. 100% oxygen) for resuscitation, hospital-based kangaroo mother care, early breastfeeding, thermal care, and surfactant therapy and application of continued distending pressure to the lungs for respiratory distress syndrome
                The research paradigm for discovery science and intervention development must be balanced to address prevention as well as improve morbidity and mortality in all settings. This review also reveals significant gaps in current knowledge of interventions spanning the continuum of maternal and fetal outcomes, and the critical need to generate further high-quality evidence for promising interventions. We carried out a prospective, randomized, double-blind, placebo-controlled study to investigate the capacity of aspirin to prevent pregnancy-induced hypertension and to alter prostaglandin metabolism. A total of 791 pregnant women with various risk factors for pre-eclamptic toxemia were screened with use of the rollover test (a comparison of blood pressure before and after the woman rolls from her left side to her back) during week 28 or 29 of gestation. Of 69 women with abnormal results (an increase in blood pressure during the rollover test), 65 entered the study and were treated with a daily dose of either aspirin (100 mg; 34 women) or placebo (31 women) during the third trimester of pregnancy. The number of women in whom pregnancy-induced hypertension developed was significantly lower among the aspirin-treated than among the placebo-treated women (4 [11.8 percent] vs. 11 [35.5 percent]; P = 0.024); the same was true for the incidence of preeclamptic toxemia (1 [2.9 percent] vs 7 [22.6 percent]; P = 0.019). The mean ratio of serum levels of thromboxane A2 to serum levels of prostacyclin metabolites after three weeks of treatment decreased by 34.7 percent in the aspirin-treated group but increased by 51.2 percent in the placebo-treated group. No serious maternal or neonatal side effects of treatment occurred in either group. We conclude that low daily doses of aspirin taken during the third trimester of pregnancy significantly reduce the incidence of pregnancy-induced hypertension and pre-eclamptic toxemia in women at high risk for these disorders, possibly through the correction of an imbalance between levels of thromboxane and prostacyclin. 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.