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Volume 141, Issue 2, Supplement, February 2012, Pages e691S-e736S
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Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only Articles
VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

https://doi.org/10.1378/chest.11-2300Get rights and content

Background

The use of anticoagulant therapy during pregnancy is challenging because of the potential for both fetal and maternal complications. This guideline focuses on the management of VTE and thrombophilia as well as the use of antithrombotic agents during pregnancy.

Methods

The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.

Results

We recommend low-molecular-weight heparin for the prevention and treatment of VTE in pregnant women instead of unfractionated heparin (Grade 1B). For pregnant women with acute VTE, we suggest that anticoagulants be continued for at least 6 weeks postpartum (for a minimum duration of therapy of 3 months) compared with shorter durations of treatment (Grade 2C). For women who fulfill the laboratory criteria for antiphospholipid antibody (APLA) syndrome and meet the clinical APLA criteria based on a history of three or more pregnancy losses, we recommend antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) over no treatment (Grade 1B). For women with inherited thrombophilia and a history of pregnancy complications, we suggest not to use antithrombotic prophylaxis (Grade 2C). For women with two or more miscarriages but without APLA or thrombophilia, we recommend against antithrombotic prophylaxis (Grade 1B).

Conclusions

Most recommendations in this guideline are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies in this population.

Section snippets

Summary of Recommendations

Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommendations sections to indicate recommendations that are newly added or have been changed since the publication of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.

2.2.1. For pregnant patients, we recommend LMWH for the prevention and treatment of VTE, instead of UFH

Methods

Table 1 describes both the question definition (ie, population, intervention, comparator, and outcomes) and the eligibility criteria for studies considered in each section of the recommendations that follow. We consider the desirable and undesirable fetal and maternal consequences of antithrombotic therapy in the following populations: (1) breast-feeding women, (2) women using assisted reproductive technology, (3) women undergoing cesarean section, (4) pregnant women with newly diagnosed VTE,

Maternal Complications of Anticoagulant Therapy

Maternal complications of anticoagulant therapy are similar to those seen in nonpregnant patients and include bleeding (for all anticoagulants) as well as heparin-induced thrombocytopenia (HIT), heparin-associated osteoporosis, bruising, local allergic reactions, and pain at injection sites for heparin-related compounds.

Vitamin K Antagonist Exposure In Utero

Vitamin K antagonists cross the placenta and have the potential to cause fetal wastage, bleeding in the fetus, and teratogenicity.47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 In a systematic review of the literature published between 1966 and 1997 that examined fetal and maternal outcomes of pregnant women with prosthetic valves, Chan and colleagues49 provided pooled estimates of risks associated with the following approaches: (1) use of vitamin K antagonists throughout pregnancy, (2)

Use of Anticoagulants in Breast-feeding Women

In order for a drug to pose a risk to the breast-fed infant, not only must it be transferred and excreted into breast milk but also it must be absorbed from the infant's gut. Drugs that are poorly absorbed are unlikely to affect the neonate. Lipid-soluble drugs with a low molecular weight that are not highly protein bound are more likely to be transferred into breast milk.96

VTE in Patients Using Assisted Reproductive Technology

Assisted reproductive technology, which refers to all treatments or procedures involving in vitro handling of human oocytes and sperm or embryos for the purpose of achieving pregnancy,114, 115 may be associated with VTE. Data regarding the frequency of VTE, however, comprise predominantly of case reports, case series, and relatively small cohort studies (Table S6).116, 117, 118, 119, 120, 121 In two large retrospective series of patients undergoing in vitro fertilization, thrombosis complicated

Risk of VTE Following Cesarean Section

The puerperium is the time of maximal daily risk of pregnancy-associated VTE.137, 138 Several observational studies have assessed the risk of VTE after cesarean section, with absolute risk estimates ranging from < 1 in 1,000 up to 18 of 1,000 cesarean deliveries.121, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148 However, studies based on hospital records and disease coding may result in an underestimation of the true incidence of symptomatic VTE.149 A Norwegian study of 59 low-risk women

Treatment of Proven Acute VTE During Pregnancy

PE remains a leading cause of maternal mortality in the western world,168, 169 and VTE in pregnancy is an important cause of maternal morbidity.168, 170, 171 Results from studies in which either all or most patients underwent accurate diagnostic testing for VTE report that the incidence of VTE ranges from 0.6 to 1.7 episodes per 1,000 deliveries.138, 139, 146, 148, 152, 172 A meta-analysis showed that two-thirds of DVT occur antepartum, with these events distributed throughout all three

Prevention of VTE in Pregnant Women With Prior DVT or PE

Compared with individuals without a history of VTE, patients with previous events are at increased risk of future episodes of DVT and PE.195 Women with a history of VTE have a threefold to fourfold higher risk of VTE during subsequent pregnancies than outside pregnancy.196 Thromboprophylaxis during pregnancy involves long-term parenteral LMWH, which is expensive, inconvenient, and painful to administer. Although bleeding, osteoporosis, and HIT are very uncommon in patients receiving

Risk of Pregnancy-Related VTE in Women With Thrombophilia

A number of studies have examined the association between hereditary thrombophilias and pregnancy-related VTE. Table 7 presents estimated and observed pooled risks for pregnant women with thrombophilia in the absence and presence of a positive family history.

In a systematic review of nine studies that assessed the risk of VTE in pregnant women with inherited thrombophilias but not necessarily a family history of VTE, all with the exception of homozygosity for the thermolabile methylene

Thrombophilia and Pregnancy Complications

Various pregnancy complications have been linked to thrombophilic states. Unfortunately, adverse pregnancy outcomes are not infrequent in the general population. Fifteen percent of clinically recognized pregnancies end in miscarriage, but total reproductive loss may be as high as 50%.244 Five percent of women experience two or more losses, and 1% to 2% have three or more consecutive losses. Other placental-mediated pregnancy complications include preeclampsia, fetal growth restriction, and

Management of Women With a History of Preeclampsia or Recurrent Fetal Loss and No Thrombophilia

Preeclampsia is associated with microvascular fibrin deposition indicative of activation of platelets and coagulation307 as well as widespread endothelial dysfunction.308, 309, 310 The manifestations of this disease are protean,310 and preeclampsia should not be considered as a single disease entity but rather as a maternal response to abnormal placentation.311, 312 Women with a thrombophilic disorder, whether it be acquired or heritable, may be more likely to develop preeclampsia, but for

Maternal and Fetal Risks Related to Anticoagulation During Pregnancy for Mechanical Prosthetic Valves

Patients with a mechanical heart valve not receiving antithrombotic therapy face a high risk of valve thrombosis and death or systemic embolism (see Whitlock et al331 in this guideline). However, as outlined in section 3.0, the use of vitamin K antagonists during pregnancy carries potential for risks to the fetus, especially if these drugs are administered during the first trimester or at term. Although LMWH or UFH can be substituted for vitamin K antagonists, doubt has been raised about their

Recommendations for Research

Although new information has been published since our last review, the available evidence in this article is still generally of low quality. Most recommendations are based on observational studies and extrapolation from other populations. There is an urgent need for appropriately designed studies to inform us of the risk of recurrent pregnancy-associated VTE and of first VTE in thrombophilic women and those undergoing cesarean section and assisted reproductive technology. Further research is

Acknowledgments

Author contributions: As Topic Editor, Dr Vandvik oversaw the development of this article, including the data analysis and subsequent development of the recommendations contained herein.

Dr Bates: contributed as Deputy Editor.

Dr Greer: contributed as a panelist.

Dr Middeldorp: contributed as a panelist.

Dr Veenstra: contributed as a resource consultant.

Dr. Prabulos: contributed as a front line clinician.

Dr Vandvik: contributed as Topic Editor.

Financial/nonfinancial disclosures: The authors of this

References (343)

  • SG Shaughnessy et al.

    A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treatment in rats

    Blood

    (1999)
  • JW Eikelboom et al.

    Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis

    Lancet

    (2000)
  • J Lepercq et al.

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

    BJOG

    (2001)
  • IA Greer et al.

    Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy

    Blood

    (2005)
  • MA Rodger et al.

    Long-term dalteparin in pregnancy not associated with a decrease in bone mineral density: substudy of a randomized controlled trial

    J Thromb Haemost

    (2007)
  • I Bank et al.

    High rate of skin complications due to low-molecular-weight heparins in pregnant women

    J Thromb Haemost

    (2003)
  • JG Hall et al.

    Maternal and fetal sequelae of anticoagulation during pregnancy

    Am J Med

    (1980)
  • D Born et al.

    Pregnancy in patients with prosthetic heart valves: the effects of anticoagulation on mother, fetus, and neonate

    Am Heart J

    (1992)
  • JL Larrea et al.

    Pregnancy and mechanical valve prostheses: a high-risk situation for the mother and the fetus

    Ann Thorac Surg

    (1983)
  • N Vitale et al.

    Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves

    J Am Coll Cardiol

    (1999)
  • HC Flessa et al.

    Placental transport of heparin

    Am J Obstet Gynecol

    (1965)
  • F Forestier et al.

    Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound

    Thromb Res

    (1984)
  • J Harenberg

    Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy

    Thromb Res

    (2007)
  • L Mazzolai et al.

    Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy

    Blood

    (2006)
  • HM Knol et al.

    Fondaparinux as an alternative anticoagulant therapy during pregnancy

    J Thromb Haemost

    (2010)
  • R Mehta et al.

    Treatment of heparin induced thrombocytopenia and thrombosis during the first trimester of pregnancy

    J Thromb Haemost

    (2004)
  • A Ekbatani et al.

    Anticoagulation with argatroban in a parturient with heparin-induced thrombocytopenia

    Int J Obstet Anesth

    (2010)
  • LM Askie et al.

    Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data

    Lancet

    (2007)
  • E Kozer et al.

    Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis

    Am J Obstet Gynecol

    (2002)
  • GD te Raa et al.

    Treatment options in massive pulmonary embolism during pregnancy; a case-report and review of literature

    Thromb Res

    (2009)
  • EL Holden et al.

    Thrombolysis for massive pulmonary embolism in pregnancy—a report of three cases and follow up over a two year period

    Thromb Res

    (2011)
  • CM Berlin et al.

    Drugs and chemicals in human milk

    Semin Fetal Neonatal Med

    (2005)
  • SL Clark et al.

    Coumarin derivatives and breast-feeding

    Obstet Gynecol

    (2000)
  • R McKenna et al.

    Is warfarin sodium contraindicated in the lactating mother?

    J Pediatr

    (1983)
  • GH Guyatt et al.

    GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

    BMJ

    (2008)
  • SD Chunilal et al.

    The APTT response of pregnant plasma to unfractionated heparin

    Thromb Haemost

    (2002)
  • JS Ginsberg et al.

    Heparin therapy during pregnancy. Risks to the fetus and mother

    Arch Intern Med

    (1989)
  • RD Hull et al.

    Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis

    N Engl J Med

    (1982)
  • RD Hull et al.

    Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis

    N Engl J Med

    (1982)
  • C Kearon et al.

    Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism

    N Engl J Med

    (2003)
  • DR Anderson et al.

    Subcutaneous heparin therapy during pregnancy: a need for concern at the time of delivery

    Thromb Haemost

    (1991)
  • RF Burrows et al.

    Incidentally detected thrombocytopenia in healthy mothers and their infants

    N Engl J Med

    (1988)
  • TE Warkentin et al.

    Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin

    N Engl J Med

    (1995)
  • Linkins L-A, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic...
  • HW de Valk et al.

    Comparing subcutaneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A randomized controlled trial

    Ann Intern Med

    (1995)
  • HN Magnani

    Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172)

    Thromb Haemost

    (1993)
  • Rubin N, Rubin J. Treatment of heparin induced thrombocytopenia with thrombosis (HITT) in pregnancy with fondaparinux...
  • R Parody et al.

    Fondaparinux (ARIXTRA) as an alternative anti-thrombotic prophylaxis when there is hypersensitivity to low molecular weight and unfractionated heparins

    Haematologica

    (2003)
  • JD Douketis et al.

    The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study

    Thromb Haemost

    (1996)
  • JS Ginsberg et al.

    Heparin effect on bone density

    Thromb Haemost

    (1990)
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    Funding/Support: The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfizer, Inc; Canyon Pharmaceuticals; and sanofi-aventis US.

    Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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