Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta‐analysis of the literature

Romualdi, Erica; Dentali, Francesco; Rancan, Elena; Squizzato, Alessandro; Steidl, L; Middeldorp, Saskia; Ageno, Walter

doi:10.1111/jth.12085

Cited by 101 publications

(80 citation statements)

References 36 publications

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“…Greer and Nelson-Piercy (2005) reported a recurrence rate of 0Á84% in women prescribed thromboprophylaxis for previous VTE, thrombophilia and/or other risk factors. Romualdi et al (2013) demonstrated a reduction in the incidence of VTE recurrence of 1Á97 (95%CI 0Á88-3Á49) in women treated with LMWH for previous VTE. Pregnant patients with either previous or current VTE were randomized to receive UFH or dalteparin; no thromboembolic complications occurred in either group and a once daily dose of dalteparin was deemed effective and safe (Pettila et al, 1999).…”

Section: Pharmacological Thromboprophylaxismentioning

confidence: 97%

The prevention of pregnancy‐related venous thromboembolism

2014

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SummaryPregnancy-related venous thromboembolism (VTE) remains one of the leading causes of maternal mortality and morbidity in the developed world. There is a lack of high-level data surrounding the use of thromboprophylaxis in pregnancy. In the UK, following the publication of the first Royal College of Obstetricians and Gynaecologists (RCOG) guideline for VTE prophylaxis during pregnancy and the puerperium in 2004, a fall in maternal deaths secondary to VTE was observed during the subsequent triennium (2006)(2007)(2008). For the first time since 1985, VTE was no longer the most common cause of maternal death. Low-molecular-weight-heparin (LMWH) is generally the agent of choice for thromboprophylaxis in this setting, and is considered safe and efficacious. The accurate risk stratification of women in order to allow the targeted provision of thromboprophylaxis is challenging. A number of international guidelines support risk assessment for pregnancyrelated VTE and the provision of LMWH for those who are deemed at sufficiently high risk. This review describes the importance of VTE in pregnancy and the puerperium, the part played by different risk factors and the role of thromboprophylaxis in this group of patients.

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Section: Pharmacological Thromboprophylaxismentioning

confidence: 97%

The prevention of pregnancy‐related venous thromboembolism

2014

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“…After the first successful reports involving the use of low-molecular-weight heparins (LMWHs) for the management of antenatal VTE >20 years ago, 3,4 LMWHs have superseded unfractionated heparin as the agents of choice for this indication. Whilst extensive reviews have concluded that LMWHs are safe during pregnancy, 5,6 many uncertainties remain on how best to manage women using an LMWH for antenatal VTE, especially whether LMWH should be prescribed once or twice a day. 7 The physiological changes associated with the gravid state are known to alter the pharmacokinetics of LMWH; the glomerular filtration rate is reported to increase by up to 50% by 15 weeks' gestation.…”

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confidence: 99%

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

et al. 2013

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Background-The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low-molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low-molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem. Method and Results-Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance.Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling. One hundred twentythree patients contributed 795 anti-Xa activities for pharmacokinetic modeling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once-versus twice-daily enoxaparin administration demonstrated that both dosing regimens would reach target 3-hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once-and twice-daily regimens exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy. Conclusions-The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered. Patel et al Population PK of Enoxaparin During Pregnancy 1463of Obstetricians and Gynaecologists (RCOG) guidelines for the management of antenatal VTE suggest a twice-daily dose of enoxaparin or dalteparin, 9 whereas the American College of Chest Physicians guidelines state that a once-or twice-daily dose could be used, acknowledging the uncertainty that exists around the optimal LMWH dosing regimen for this indication. 10 The evidence for increasing the total daily dose or dosing frequency during pregnancy is based on small, historical, observational studies.11-27 Prescribing a twice-daily dosing regimen of LMWH has significant implications for women with respect to injection burden, particularly if the VTE event occurs early during pregnancy. Clinical Perspective on p 1469We developed a population pharmacokinetic model 28 to better understand the specific pharmacokinetic changes in LMWH during pregnancy and, through pharmacokinetic simulation, determined the optimal dosing strategy to use during pregnancy for the treatment of antenatal VTE. MethodsPregnant women ≥18 years of age who were referred to the specialist thrombophilia clinic at King's College Hospital were eligible for recruitment to the study. King's Co...

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“…Although a Cochrane Review stated that there was no evidence from randomised controlled trials regarding the effi cacy of anticoagulant therapy for DVT in pregnancy [2], two systemic reviews of LMWH use in pregnant women have confi rmed their efficacy and safety, which were consistent with those in nonpregnant women [3,4]. Compared to unfractionated heparin (UFH), LMWH were associated with a substantially lower risk of adverse side eff ects, such as heparin-induced thrombocytopenia (HIT), haemorrhage, and osteoporosis [3 -7].…”

Section: Anticoagulant Therapy During Pregnancymentioning

confidence: 99%

Treatment of pregnancy-associated venous thromboembolism - position paper from the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH)

Linnemann

Scholz

Rott

et al. 2016

Vasa

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Summary: Venous thromboembolism (VTE) is a major cause of maternal morbidity during pregnancy and the postpartum period. However, because there is a lack of adequate study data, management strategies for pregnancy-associated VTE must be deduced from observational studies and extrapolated from recommendations for non-pregnant patients. In this review, the members of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH) have summarised the evidence that is currently available in the literature to provide a practical approach for treating pregnancy-associated VTE. Because heparins do not cross the placenta, weight-adjusted therapeutic-dose low molecular weight heparin (LMWH) is the anticoagulant treatment of choice in cases of acute VTE during pregnancy. No differences between once and twice daily LMWH dosing regimens have been reported, but twice daily dosing seems to be advisable, at least peripartally. It remains unclear whether determining dose adjustments according to factor Xa activities during pregnancy provides any benefi t. Management of delivery deserves attention and mainly depends on the time interval between the diagnosis of VTE and the expected delivery date. In particular, if VTE manifests at term, delivery should be attended by an experienced multidisciplinary team. In lactating women, an overlapping switch from LMWH to warfarin is possible. Anticoagulation should be continued for at least 6 weeks postpartum or for a minimum period of 3 months. Although recommendations are provided for the treatment of pregnancy-associated VTE, there is an urgent need for well-designed prospective studies that compare different management strategies and defi ne the optimal duration and intensity of anticoagulant treatment. Anticoagulant therapy during pregnancyLow-molecular-weight heparins (LMWH) are considered the anticoagulants of choice in pregnancy-associated VTE because LMWH do not cross the placenta and do not appear at signifi cant levels in breast milk. Although a Cochrane Review stated that there was no evidence from randomised controlled trials regarding the effi cacy of anticoagulant therapy for DVT in pregnancy [2], two systemic reviews of LMWH use in pregnant women have confi rmed their efficacy and safety, which were consistent with those in nonpregnant women [3,4]. Compared to unfractionated heparin (UFH), LMWH were associated with a substantially lower risk of adverse side eff ects, such as heparin-induced thrombocytopenia (HIT), haemorrhage, and osteoporosis [3 -7]. However, UFH may be considered an alternative if LMWH cannot be used or if UFH seems to be advantageous over LMWH, e.g., in women at high risk of bleeding complications or in women with severe renal impairment. Women with confi rmed PE and haemodynamic compromise who are candidates for subsequent thrombolysis should also receive UFH during the initial phase until defi nitive treatment decisions are reached [1]. Data obtained from non-pregnant patients have confi rmed that LMWH are at least as eff ective...

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Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta‐analysis of the literature

Cited by 101 publications

References 36 publications

The prevention of pregnancy‐related venous thromboembolism

The prevention of pregnancy‐related venous thromboembolism

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Treatment of pregnancy-associated venous thromboembolism - position paper from the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH)

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