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Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physician Evidence-Based Clinical Practice Guidelines Online Only ArticlesVTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
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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
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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.
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