Prophylactic and therapeutic enoxaparin during pregnancy: indications, outcomes and monitoring

OBJECTIVES: To evaluate the efficacy and safety of prophylactic and therapeutic enoxaparin in pregnancy. STUDY DESIGN: Three-year prospective audit. SETTING: Tertiary level obstetric hospital. POPULATION: Fifty-two women who received subcutaneous enoxaparin, either a prophylactic dose (40 mg daily) in 26 pregnancies or therapeutic dose (1 mg/kg twice daily) in 32 pregnancies. MATERIALS AND METHODS: Pregnant women treated with enoxaparin were prospectively entered into a register. Data were retrieved by case note review. MAIN OUTCOME MEASURES: Pregnancy outcomes, treatment complications and anti-Xa levels. RESULTS: In the prophylactic group there were no fetal losses, thromboembolic events or complications related to enoxaparin. In the therapeutic group there were four first trimester miscarriages, a termination and 27 live births. Therapeutic enoxaparin prevented further thromboembolism without complications. One woman was treated with intermediate dose enoxaparin when she presented at 5 weeks' gestation on warfarin and 7 weeks after a venous thromboembolism. She developed a recurrent pulmonary embolus 3 weeks later and was subsequently treated with therapeutic enoxaparin. In the therapeutic group the enoxaparin dose/kg correlated poorly with anti-Xa levels, and dose adjustments were made. Therapeutic mean (SD) trough and peak anti-Xa levels were 0.33 U/mL (0.14) and 0.86 U/mL (0.24) in the first trimester and 0.48 U/mL (0.19) and 0.84 U/mL (0.23) in the third trimester. CONCLUSIONS: In the present series, prophylactic and therapeutic enoxaparin treatment during pregnancy was effective and safe. Studies are required to determine the optimal duration of treatment with therapeutic enoxaparin following venous thromboembolism in pregnancy and the clinical relevance of anti-Xa monitoring.     

Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy

Objective To assess the safety and efficacy of enoxaparin use for thromboprophylaxis or treatment of venous thromboembolism during pregnancy.
Design Retrospective review of casenotes of women who received enoxaparin during pregnancy.
Setting Obstetric Medicine Unit at Glasgow Royal Maternity Hospital.
Sample Data were obtained on 57 pregnancies in 50 women over six years.
Methods Information was obtained from case records in relation to outcome measures, the presence of underlying thrombophilia and indication for anticoagulation.
Main outcome measures Incidences of venous thromboembolism, haemorrhage, thrombocytopenia, peak plasma anti-factor Xa levels and symptomatic osteoporosis.
Results There were no thromboembolic events in the thromboprophylaxis group. There were no incidences of heparin-induced thrombocytopenia. Twenty-two women had spinal or epidural anaesthesia and no complications were encountered. There was one instance of antepartum haemorrhage following attempted amniotomy in a woman with previously unknown vasa praevia. Two women sustained postpartum haemorrhage, both secondary to vaginal lacerations, resulting in blood loss > 1000 mL. Blood loss following caesarean section was not excessive. No instances of vertebral or hip fracture were encountered. The median peak plasma anti-factor Xa level on a dose of 40 mg once daily was 0.235 U/mL; peak plasma anti-factor Xa levels were not affected by gestational age.
Conclusions The use of enoxaparin in pregnancy is associated with a low incidence of complications and a dose of 40 mg once daily throughout pregnancy provides satisfactory anti-factor Xa levels and appears effective in preventing venous thromboembolism.     

Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin

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, 20mg and 40mg, 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.     

Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy

Objective To evaluate the effect and dose of dalteparin given to pregnant women with acute venous thromboembolism.
Design An observational study of pregnant women in Norway.
Setting Delivery and haematological departments in Norway.
Population Twenty women, aged 22–41 years, with acute venous thromboembolism verified by objective means.
Methods Patients were treated with dalteparin from diagnosis until delivery. Treatment was monitored with anti-activated factor Xa (anti-Xa) activity, and the dose was adjusted to achieve target 0.5–1.0 U/mL 2–3 hours post-injection.
Main outcome measure Anti-Xa activity and side effects.
Result None of the patients suffered recurrent venous thromboembolism or major bleeding complications. In 9 of 13 women starting with conventional dose of dalteparin (100 iu/kg bd), dose escalation was necessary to reach target anti-Xa activity. None of the six women who started with 105–118 iu/kg bd required dose escalation. One woman who started with 133 iu/kg bd required dose reduction. Bioaccumulation of dalteparin was not observed.
Conclusion Our study suggests that dalteparin may be used for the treatment of acute venous thromboembolism in pregnancy. Approximately 10–20% higher doses of dalteparin may be needed as compared with non-pregnant individuals.     

Enoxaparin treatment in women with mechanical heart valves during pregnancy

OBJECTIVE: This prospective audit reports pregnancy outcomes, anticoagulation complications, and anti-Xa levels in women with mechanical heart valves who were treated with therapeutic enoxaparin plus aspirin during pregnancy. STUDY DESIGN: Between 1997 and 1999, 11 women with mechanical heart valves were treated with enoxaparin, 1 mg/kg twice daily, and aspirin, 100 to 150 mg daily during 14 pregnancies. Predose and 4-hour postdose anti-Xa levels were monitored monthly. RESULTS: There were 9 live births, 3 miscarriages, and 2 terminations. In 48 months of enoxaparin treatment, one woman who had a documented valve thrombosis when she presented at 8 weeks' gestation also had a valve thrombosis at 20 weeks' gestation. There were no enoxaparin-related hemorrhagic complications. Mean (SD) anti-Xa levels were 0.46 (0.12) U/mL predose and 0.89 (0.22) U/mL 4 hours postdose. CONCLUSION: Successful pregnancy outcome may be achieved with therapeutic subcutaneous enoxaparin, but its efficacy at preventing valve thrombosis remains uncertain. Further data are required before use of enoxaparin during pregnancy in women with mechanical heart valves can be recommended.     

Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies

Objective To assess the maternal, fetal and neonatal safety of enoxaparin in pregnant women who require antithrombotic therapy.
Design Retrospective analysis of case notes of women who received enoxaparin during pregnancy, irrespective of dose, duration and reason for treatment.
Setting Fifty-five French perinatal centres.
Sample Data from 624 pregnancies in 604 women between 1988 and 1997. The incidence of previous thromboembolism was 29.8%, known thrombophilia 15.2%.
Methods Indication, regimen of enoxaparin and outcome measures were reported for each pregnancy. Information was obtained from case records, validated by research staff and analysed by an independent scientific committee.
Main outcome measures Incidence, seriousness and causality of maternal, fetal and neonatal adverse events, pregnancy outcome, and incidence of venous thromboembolism.
Results Enoxaparin was administered for treatment of an acute episode in 49 cases and for thromboprophylaxis in 574 cases. Serious maternal haemorrhage occurred in 11 cases during pregnancy (1.8%), one being reasonably related to enoxaparin, and in nine cases at delivery (1.4%), all unrelated to enoxaparin. Maternal thrombocytopenia was reported in 10 cases (1.6%), two being serious but unrelated to enoxaparin. Eight pregnancies ended in stillbirth (1.1%). Among the 693 live births, 17 major congenital abnormalities (2.5%) and 10 serious neonatal haemorrhages (1.4%) were reported. None of the fetal or neonatal adverse events was related to enoxaparin. Eight venous thromboembolic events (1.3%) were reported.
Conclusions The incidence of adverse events reported could be explained by the high risk profile of the study population. Overall, this retrospective study suggests enoxaparin is well tolerated during pregnancy.     

Anti-factor Xa plasma levels in pregnant women receiving low molecular weight heparin thromboprophylaxis

OBJECTIVE: To report the incidence of prophylactic, subprophylactic, and supraprophylactic anti-factor Xa activity in pregnant patients receiving low molecular weight heparin for venous thromboembolism prophylaxis, and to evaluate whether maternal weight, body mass index, age, gestational age, or the low molecular weight heparin dose correlated with anti-factor Xa levels. METHODS: We reviewed 321 anti-factor Xa levels in 77 patients from one Maternal-Fetal Medicine faculty practice. All patients were administered low molecular weight heparin that subsequently was adjusted based upon serial assessment of peak plasma (at 4 hours postinjection) anti-factor Xa levels at less than 36 weeks gestation. Targeted prophylactic range of peak plasma anti-factor Xa level was 0.2-0.4 units/mL. RESULTS: Only 59% of anti-Xa concentrations were in the prophylactic range, whereas 26% were subprophylactic, and 15% were supraprophylactic. Anti-Xa values were not significantly more likely to be prophylactic in early compared with late pregnancy, obese compared with nonobese patients, or in patients receiving a weight-based minimal dose compared with patients receiving less than a weight-based minimal dose. Anti-factor Xa levels did not correlate with maternal age, weight, body mass index, or gestational age, but there was a positive correlation with the percent of the minimal weight-based dose. CONCLUSION: Even with enhanced low molecular weight heparin dosing, 26% of patients have subprophylactic anti-factor Xa levels. Serial anti-factor Xa assessment for dose adjustment should be considered for all pregnant women receiving low molecular weight heparin.     

Antithrombotic therapy during pregnancy.

Antithrombotic therapy is required during pregnancy for the prevention and treatment of venous and arterial thromboembolism and for the prevention of pregnancy loss in women at risk. The choice of anticoagulant for venous thromboembolism during pregnancy is limited to unfractionated heparin or low molecular weight heparin because the use of warfarin is relatively contraindicated. Much of the information surrounding the pharmacokinetics and dosing of unfractionated heparin and low molecular weight heparin obtained from non-pregnant patients has been applied to pregnant women. Whether this is appropriate in the presence of significant physiological changes in pregnancy is unclear. Specific to pregnancy and unfractionated heparin use, activated partial prothrombin time may be unreliable. In addition, the appropriate dosing of low molecular weight heparin is uncertain. Because venous thromboembolism can cause significant maternal morbidity and mortality, these important issues surrounding appropriate drug dosing of anticoagulants should be addressed.     

Comparison of enoxaparin and standard heparin in gynaecologic oncologic surgery: a randomised prospective double-blind clinical study.

OBJECTIVE: This study aimed to compare the haemorrhagic complications and efficacy of enoxaparin, a low molecular weight heparin (LMWH), and conventional standard heparin (SH) in gynaecological oncologic surgery. MATERIALS METHODS: A double blind, randomised trial was performed on 102 consecutive women undergoing gynaecologic cancer surgery with pelvic and paraaortic lymphadenectomy. The women were separated into those who were given 2,500 IU enoxaparin once daily and SH in a dose of 5,000 IU three times daily. The groups were analysed for intraoperative blood loss, drainage, transfusion requirements, perioperative haemoglobin decrease, wound haematoma, and clinical deep venous thrombosis. RESULTS: The two groups were well matched for age, weight, and other factors, which could predispose to the development of deep venous thrombosis (DVT) and haemorrhage. No patient developed clinical significant DVT, wound haematoma or intra-abdominal bleeding. There was no significant difference in bleeding complications between the two regimens. The antiFXa level in the plasma was correlated strongly with patient weight. CONCLUSIONS: A dose of 2,500 IU enoxaparin/day does not cause more bleeding complications than SH 5,000 IU three times daily when used to prevent thrombosis. However, the dose of enoxaparin must be adjusted to the patient's weight.     

Management of thromboembolism in pregnancy

The incidence of venous thromboembolism is increased during pregnancy and the postpartum period. This risk is high for women with documented hereditary or acquired risk factors who have experienced a prior thrombotic event. These individuals require a minimum of prophylactic dose anticoagulation with unfractionated or low molecular weight heparin during pregnancy, with anticoagulation continuing for 4 to 6 weeks postpartum. Women receiving therapeutic dose anticoagulation with warfarin before pregnancy for a hereditary or acquired condition should be transitioned to therapeutic doses of unfractionated heparin or low molecular weight heparin before or within 6 weeks of becoming pregnant, and can then resume warfarin postpartum. Women experiencing a thromboembolic event during pregnancy should receive therapeutic treatment with unfractionated heparin or low molecular weight heparin during pregnancy, with anticoagulation continuing for 4 to 6 weeks postpartum, and for a total of at least 6 months.     

Treatment of deep venous thrombosis in pregnant women

The recommended dosage of tinzaparin in the treatment of thromboembolism during pregnancy is 175 IU/kg/day, as for non-pregnant subjects. In clinical practice, we have experienced a need for a higher dosage, especially in the initial phase of the treatment of deep vein thrombosis, based on four-hour post-dose measurements of anti-Xa activity. Twenty-two pregnant patients with a confirmed deep venous thrombosis were treated with tinzaparin either in a once- or twice-daily regimen. Four-hour post-dosage plasma anti-Xa activity was measured in 357 sequential blood samples during treatment. An higher dosage than recommended, was required to maintain anti-Xa activity in the target range. We suggest that the starting dosage should be 250 IU/kg/day in a twice-daily regimen, and that the dose in the initial phase be adjusted by daily monitoring of anti-Xa.     

Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin.

OBJECTIVES: To determine if a prophylactic dose of dalteparin, 5000 IU daily, and if the adjusted-weight dalteparin therapeutic dose of 100 IU/kg twice daily are appropriate in pregnancy. METHOD: Anti-Xa activity levels were used to assess prophylactic (33 women) and therapeutic (15 women) dalteparin dosage throughout pregnancy. Analysis of variance was used and P-values less than 0.05 were considered statistically significant. RESULTS: In the prophylactic group, anti-Xa activity levels did not vary significantly throughout pregnancy (P=0.15). The initial dalteparin dose was modified on the first anti-Xa activity measurement in eight women, whose weight was statistically different from those remaining on the initial dose (P<0.001). The adjusted-weight therapeutic dalteparin dose induced adequate anti-Xa activity levels. CONCLUSIONS: Dalteparin, 5000 IU daily, is suitable for most pregnant women and does not need to be modified in the third trimester. A therapeutic dalteparin dose adjusted according to pregnancy weight is appropriate.     

A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation

OBJECTIVE: The purpose of this study was to determine whether standard therapeutic doses of dalteparin maintain peak therapeutic levels of anticoagulation during pregnancy. STUDY DESIGN: This was a prospective trial in which 13 pregnancies that required therapeutic anticoagulation were treated with dalteparin 100 U/kg every 12 hours; peak and trough (predose) low molecular weight heparin (anti-Xa activity) levels were monitored every 2 weeks. Dosage adjustments were made to maintain peak anti-Xa activity between 0.5 and 1.0 IU/ml. Bone density and bone turnover markers were measured. RESULTS: A total of 250 peak and trough low-molecular-weight heparin (LMWH) levels were obtained. Eighty-five percent of pregnancies (11/13) required an upward dosage adjustment. Trough levels were in the therapeutic range only 9% of the time, despite the maintenance of therapeutic peak levels. Bone resorption markers and density were unchanged in singleton pregnancies. CONCLUSION: Dalteparin dosing, based on weight alone, every 12 hours is inadequate to maintain most pregnant women in the therapeutic range throughout pregnancy as measured by anti-Xa activity. Trough levels are rarely in the therapeutic range, despite maintenance of therapeutic peak levels. These notable changes in low molecular weight heparin peak may explain reported failures in pregnancy.     

Heparin levels to guide thromboembolism prophylaxis during pregnancy

OBJECTIVE: Our purpose was to determine the dose of heparin required in pregnant women to achieve the same heparin levels as standard doses of 5000 units given subcutaneously every 12 hours in the nonpregnant population.STUDY DESIGN: Fourteen pregnant women placed on heparin prophylaxis for a history of thromboembolism had blood drawn for 64 anti-Xa level determinations in the second and third trimesters. Heparin doses were adjusted in an attempt to achieve a midinterval or peak level of 0.05 to 0.25 U/ml, which corresponds to the range seen in nonpregnant patients given standard doses of 5000 units subcutaneously every 12 hours.RESULTS: A standard heparin dose of 5000 units given subcutaneously every 12 hours was inadequate to achieve the desired range in this pregnant population. In five of nine second-trimester pregnancies 7500 units given subcutaneously every 12 hours was inadequate to attain this range. In six of 13 third-trimester pregnancies, > 10,000 units subcutaneously every 12 hours was needed.CONCLUSIONS: Heparin requirements may increase and are highly variable in patients during pregnancy. Until appropriate clinical outcomes trials can determine optimal dosing, measuring anti-Xa activity may be useful to guide therapy.     

Tinzaparin sodium for thrombosis treatment and prevention during pregnancy

OBJECTIVE: This study was undertaken to assess the pharmacodynamic profile, safety, and efficacy of tinzaparin during pregnancy. STUDY DESIGN: Fifty-four pregnant women, 12 for treatment of thrombosis and 42 for thromboprophylaxis, received tinzaparin by once daily injection. Four-hour postdose anti-Xa results were analyzed by use of repeated measures statistical methods. RESULTS: One woman (3.4%) on the 175 anti-Xa U/kg dose and three women (20%) on the 50 anti-Xa U/kg dose required a dose increase during the initial dose titration phase to achieve target anti-Xa activity. No thrombotic events occurred. CONCLUSION: The 175 anti-Xa U/kg dose is appropriate for treatment and for high-risk thromboprophylaxis throughout pregnancy. In pregnant women at moderate risk of thrombosis, a higher tinzaparin dose is required than in the nonpregnant state and 75 anti-Xa U/kg appears to be appropriate. The majority of women do not need a dose increase with advancing gestation.     

Inherited thrombophilias and anticoagulation in pregnancy

Thromboprophylaxis, primary or secondary, should be considered in selected pregnant women with inherited thrombophilias; such women may be divided into high-, medium- and low-risk categories on the basis of the specific thrombophilic defect and any personal or family history of venous thromboembolism (VTE). Women at high risk of VTE should receive treatment doses of low-molecular-weight heparin (LMWH) throughout pregnancy and should remain on anticoagulation for 6 weeks postpartum, or, where appropriate, long-term. Women at moderate risk should be treated with prophylactic fixed-dose LMWH throughout pregnancy and for 6 weeks postpartum. Women at low risk should receive prophylactic fixed-dose LMWH for 6 weeks postpartum, and low-dose aspirin LDA should be considered during pregnancy. LWMH offers important advantages over unfractionated heparin (UFH); heparin-induced thrombocytopaenia (HIT) and osteopaenia are rarely seen. For treatment doses of LMWH, dosage adjustment based on anti-Xa levels is usually required as pregnancy progresses. Warfarin should be avoided throughout pregnancy. LMWH, UFH and warfarin are safe for breast-feeding mothers.     

A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy

OBJECTIVE: To assess the maternal response to low molecular weight heparin during pregnancy, by estimation of plasma anti-Xa activity, at three specified gestation points and in the nonpregnant state. METHODS: A longitudinal, prospective, observational study was set in a tertiary referral recurrent miscarriage clinic. Twenty-four women, attending consecutively, were invited to participate and gave informed consent. Each woman had a history of recurring pregnancy loss and positive preconception screening for antiphospholipid syndrome. After confirmation of a viable pregnancy all subjects began taking 5000 IU of dalteparin once daily subcutaneously. Serial measurement of plasma anti-Xa activity after administration of dalteparin was performed at three standard gestation points (12, 24, and 36 weeks) and in the nonpregnant state (6 weeks postpartum). RESULTS: Peak anti-Xa levels occurred at 4 hours postbolus in pregnancy, as compared with 2 hours in the nonpregnant state. The mean anti-Xa levels at 12, 24, and 36 weeks' gestation were significantly reduced, at 2 hours postinjection, as compared with the nonpregnant state (P <.001, P <.01, P <.001, respectively). The lowest dose-response curve was at 36 weeks' gestation. A repeated-measures analysis of variance found a significant difference (P <.05) between the 36-week group and the postterm group but not between any of the other groups. CONCLUSION: During pregnancy, differences in the pharmacokinetics of low molecular weight heparin were observed, with an overall reduction in anti-Xa activity. On the basis of this study it is questionable to extrapolate dosing and lack of dose monitoring, in pregnant women, using data derived from a nonpregnant population.     

Use of Low Molecular Weight Heparin in Acute Venous Thromboembolic Events in Pregnancy

Objective: To compare the maternal and neonatal outcomes arising from the use of low molecular weight heparin (LMWH) or unfractioned heparin (UFH) in the treatment of acute venous thromboembolism (VTE) in pregnancy.Study Design: A retrospective review of the charts of all women treated for acute VTE in pregnancy at the Ottawa Hospital from January 1990 to December 1999.Results: Twenty-three cases were identified, of which 11 were treated with LMWH and 12 with UFH. Maternal and fetal outcomes were similar between the two groups. Hospital length of stay was shorter in the LMWH group. There was no difference in delivery management between the two groups. There was minor bleeding in 2 women in the UFH group and none in the LMWH group. There was one recurrent VTE during treatment in each of the groups.Conclusion: There is no difference in complication rate between LMWH and UFH in the treatment of acute VTE in pregnancy.     

Use of low molecular weight heparin for prophylaxis and treatment of thromboembolism in pregnancy.

Low molecular weight heparin (LMWH) preserves the antithrombotic action but not the anticoagulant activity of heparin. LMWH is safe, does not cross the placenta and is administered as a single daily injection. We report our experience with 6 pregnant women given LMWH for treatment or prophylaxis of thromboembolism. The drug was successfully given to 5 women for periods of 6 weeks--6 months and no thromboembolic complications occurred during pregnancy or pueperium. There were no hemorrhagic complications and no excessive bleeding was observed during delivery. The sixth patient relapsed after 6 weeks of therapy. This patient also showed resistance to standard heparin administered intravenously at a very high dose. LMWH should be considered an alternative to standard heparin in pregnant women requiring antithrombotic prophylaxis and therapy.     

Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database

Objective To determine the incidence of venous thromboembolism in pregnancy and the puerperium and to identify risk factors for pregnancy-related venous thromboembolism.
Design Cohort study and case–control study.
Setting London, UK.
Population 395,335 women with live births or pregnancies of 24 or more weeks of gestation between 1988 and 1997.
Methods Data extraction from the St Mary's Maternity Information System database. Random sample of 5% for case–control study.
Main outcome measures Incidence of venous thromboembolism; odds ratios for variables associated with venous thromboembolism.
Results The incidence of venous thromboembolism was 85/100,000 maternities. There were approximately twice as many postpartum as antepartum events. Blood group A, multiple pregnancy, caesarean section, cardiac disease, delivery at gestational age of <36 weeks, a body mass index of ≥25, or more and maternal age of 35 or over were all found to increase incidence of venous thromboembolism.
Conclusions Although venous thromboembolism is the leading cause of maternal deaths in the UK, it is still a rare event. Most of these events are deep vein thromboses occurring in the postpartum period. Antenatally multiple birth is an important risk factor. Postnatally women who have had a caesarean section, premature delivery or history of cardiac disease should be assessed carefully for venous thromboembolism.