Low-Molecular-Weight Heparin in High-Risk Pregnancy
Low-Molecular-Weight Heparin in High-Risk Pregnancy
Study Objective . To evaluate dosing requirements and monitoring patterns of low-molecular-weight heparin (LMWH)when used in high-risk pregnancy.
Design. Retrospective, observational, cohort study.
Setting. University-affiliated medical center.
Patients. Forty-nine women treated with LMWH between 2001 and 2005 for
either prophylaxis or treatment of venous thromboembolism during pregnancy and monitored with antifactor Xa activity.
Measurements and Main Results. Data were obtained on 53 pregnancies in the 49 women. The primary outcome was change in dosing requirements of LMWH throughout pregnancy as determined by the corresponding antifactor Xa activity peak levels. Mean starting doses of twice-daily enoxaparin and doses most proximate to delivery were 39.2 mg (range 30–60 mg) and 55.0 mg (range 30–100 mg, p=0.06), respectively, for the prophylaxis group and 83.0 mg (range 30–180 mg) and 85.7 mg (range 30–160 mg, p=0.41), respectively, for the therapeutic group. Weight-based mean starting doses and doses most proximate to delivery were 0.46 and 0.62 mg/kg (p=0.03), respectively, for the prophylaxis group and 0.90 and 0.87 mg/kg (p=0.29), respectively, for the therapeutic group. Dose changes were required in 9 (69%) of 13 pregnancies and 21 (55%) of 38 pregnancies (data from two of the 40 pregnancies were excluded—one in a patient receiving dalteparin, and one in a patient with mitral valve replacement who had higher antifactor Xa goals) in the prophylaxis and therapeutic groups, respectively, to achieve target antifactor Xa activity. The weight-based prophylactic dose was consistently 0.6 mg/kg in all three trimesters, achieving a mean ± SD target antifactor Xa activity of 0.39 ±0.18 units/ml, whereas the therapeutic dose was 0.9 mg/kg to maintain antifactor Xa activity of 0.71 ± 0.22 units/ml.
Conclusion. Dose changes for LMWH throughout pregnancy as guided by antifactor Xa activity were common. A significant increase in the LMWH dose requirements in the prophylactic group suggests that more frequent monitoring of antifactor Xa activity may be appropriate in pregnant patients to maintain target anticoagulant levels.
Thromboembolism is the leading cause of maternal morbidity and mortality in developed countries. The overall incidence of deep vein thrombosis and pulmonary embolism during pregnancy has been estimated at 1/1000 pregnancies. Low-molecular-weight heparin (LMWH) has several advantages over unfractionated heparin, including a prolonged plasma half-life that may allow once- or twice-daily dosing, a more predictable anticoagulant response that may obviate the need for routine laboratory moni-toring, and a decreased frequency of heparin-induced thrombocytopenia.
The 2008 American College of Chest Physicians (ACCP) clinical practice guidelines provide recommendations for the use of LMWH during pregnancy. In addition, the American College of Obstetricians and Gynecologists issued a committee opinion in 2002 stating that LMWH is safe and efficacious in pregnant women and recently reported LMWH treatment options for those with an inherited thrombophilia. For initial treatment of venous thromboembolism, a weight-adjusted therapeutic regimen such as enoxaparin 1 mg/kg every 12 hours is recommended. With pregnancy progression, there are increases in maternal weight, increases in renal clearance of LMWH, and increases in the volume of distribution of LMWH, possibly necessitating adjustments in dosing. To ensure adequate anticoagulation throughout pregnancy, dosing options include either adjusting the dosage in proportion to the actual weight change, or performing antifactor Xa activity monitoring (as 4-hr peak levels after steady state has been achieved) and adjusting the LMWH dosage to achieve a therapeutic antifactor Xa activity of approximately 0.5–1.0 units/ml.
For venous thromboembolism prophylaxis, the 2004 ACCP recommendations suggested targeting a prophylactic antifactor Xa activity to achieve a peak level of 0.2–0.6 units/ml, but this range is not included as part of the 2008 recommendations, with no specific range currently recommended. Instead, the 2008 ACCP recommendations define a prophylactic dose as enoxaparin 40 mg every 24 hours, dalteparin 5000 units every 24 hours, or tinzaparin 4500 units every 24 hours, with a statement that at extremes of body weight, modifications of the dose may be required. New in the 2008 ACCP recommendations is an intermediate-dose LMWH regimen, consisting of enoxaparin 40 mg every 12 hours or dalteparin 5000 units every 12 hours. The concept of using a target antifactor Xa level for venous thromboembolism prophylaxis remains controversial, with currently acceptable alternatives including the option for the previously defined prophylactic dose, using an intermediate-dose LMWH, or periodic monitoring of the antifactor Xa activity during pregnancy. The increased renal clearance of LMWH during pregnancy has prompted the latter approach of periodic antifactor Xa activity monitoring at our institution. However, the need for this practice remains controversial, since the ideal target range for prophylaxis is unclear and dosage adjustments may not, in fact, impact the safety or efficacy of anticoagulant prophylaxis.
Although dosing recommendations for LMWH in pregnancy are fairly well described, monitoring guidelines to attain acceptable anticoagulant safety and efficacy are still needed. The primary objective of this study was to evaluate the dosing requirements and monitoring patterns when LMWH is used for therapeutic or prophylactic anticoagulation during pregnancy.
Abstract and Introduction
Abstract
Study Objective . To evaluate dosing requirements and monitoring patterns of low-molecular-weight heparin (LMWH)when used in high-risk pregnancy.
Design. Retrospective, observational, cohort study.
Setting. University-affiliated medical center.
Patients. Forty-nine women treated with LMWH between 2001 and 2005 for
either prophylaxis or treatment of venous thromboembolism during pregnancy and monitored with antifactor Xa activity.
Measurements and Main Results. Data were obtained on 53 pregnancies in the 49 women. The primary outcome was change in dosing requirements of LMWH throughout pregnancy as determined by the corresponding antifactor Xa activity peak levels. Mean starting doses of twice-daily enoxaparin and doses most proximate to delivery were 39.2 mg (range 30–60 mg) and 55.0 mg (range 30–100 mg, p=0.06), respectively, for the prophylaxis group and 83.0 mg (range 30–180 mg) and 85.7 mg (range 30–160 mg, p=0.41), respectively, for the therapeutic group. Weight-based mean starting doses and doses most proximate to delivery were 0.46 and 0.62 mg/kg (p=0.03), respectively, for the prophylaxis group and 0.90 and 0.87 mg/kg (p=0.29), respectively, for the therapeutic group. Dose changes were required in 9 (69%) of 13 pregnancies and 21 (55%) of 38 pregnancies (data from two of the 40 pregnancies were excluded—one in a patient receiving dalteparin, and one in a patient with mitral valve replacement who had higher antifactor Xa goals) in the prophylaxis and therapeutic groups, respectively, to achieve target antifactor Xa activity. The weight-based prophylactic dose was consistently 0.6 mg/kg in all three trimesters, achieving a mean ± SD target antifactor Xa activity of 0.39 ±0.18 units/ml, whereas the therapeutic dose was 0.9 mg/kg to maintain antifactor Xa activity of 0.71 ± 0.22 units/ml.
Conclusion. Dose changes for LMWH throughout pregnancy as guided by antifactor Xa activity were common. A significant increase in the LMWH dose requirements in the prophylactic group suggests that more frequent monitoring of antifactor Xa activity may be appropriate in pregnant patients to maintain target anticoagulant levels.
Introduction
Thromboembolism is the leading cause of maternal morbidity and mortality in developed countries. The overall incidence of deep vein thrombosis and pulmonary embolism during pregnancy has been estimated at 1/1000 pregnancies. Low-molecular-weight heparin (LMWH) has several advantages over unfractionated heparin, including a prolonged plasma half-life that may allow once- or twice-daily dosing, a more predictable anticoagulant response that may obviate the need for routine laboratory moni-toring, and a decreased frequency of heparin-induced thrombocytopenia.
The 2008 American College of Chest Physicians (ACCP) clinical practice guidelines provide recommendations for the use of LMWH during pregnancy. In addition, the American College of Obstetricians and Gynecologists issued a committee opinion in 2002 stating that LMWH is safe and efficacious in pregnant women and recently reported LMWH treatment options for those with an inherited thrombophilia. For initial treatment of venous thromboembolism, a weight-adjusted therapeutic regimen such as enoxaparin 1 mg/kg every 12 hours is recommended. With pregnancy progression, there are increases in maternal weight, increases in renal clearance of LMWH, and increases in the volume of distribution of LMWH, possibly necessitating adjustments in dosing. To ensure adequate anticoagulation throughout pregnancy, dosing options include either adjusting the dosage in proportion to the actual weight change, or performing antifactor Xa activity monitoring (as 4-hr peak levels after steady state has been achieved) and adjusting the LMWH dosage to achieve a therapeutic antifactor Xa activity of approximately 0.5–1.0 units/ml.
For venous thromboembolism prophylaxis, the 2004 ACCP recommendations suggested targeting a prophylactic antifactor Xa activity to achieve a peak level of 0.2–0.6 units/ml, but this range is not included as part of the 2008 recommendations, with no specific range currently recommended. Instead, the 2008 ACCP recommendations define a prophylactic dose as enoxaparin 40 mg every 24 hours, dalteparin 5000 units every 24 hours, or tinzaparin 4500 units every 24 hours, with a statement that at extremes of body weight, modifications of the dose may be required. New in the 2008 ACCP recommendations is an intermediate-dose LMWH regimen, consisting of enoxaparin 40 mg every 12 hours or dalteparin 5000 units every 12 hours. The concept of using a target antifactor Xa level for venous thromboembolism prophylaxis remains controversial, with currently acceptable alternatives including the option for the previously defined prophylactic dose, using an intermediate-dose LMWH, or periodic monitoring of the antifactor Xa activity during pregnancy. The increased renal clearance of LMWH during pregnancy has prompted the latter approach of periodic antifactor Xa activity monitoring at our institution. However, the need for this practice remains controversial, since the ideal target range for prophylaxis is unclear and dosage adjustments may not, in fact, impact the safety or efficacy of anticoagulant prophylaxis.
Although dosing recommendations for LMWH in pregnancy are fairly well described, monitoring guidelines to attain acceptable anticoagulant safety and efficacy are still needed. The primary objective of this study was to evaluate the dosing requirements and monitoring patterns when LMWH is used for therapeutic or prophylactic anticoagulation during pregnancy.
