VTE in pregnancy treatment

Pulmonary embolism (PE) is a leading cause of maternal death, particularly in developed countries. Pregnancy is a hypercoagulable state due to an increase in venous stasis; increase in procoagulant factors, such as fibrinogen and factors V, VIII, IX, and X; and decreased anticoagulant activity due to a decrease in protein S concentration, an increase in activated protein C resistance, and decrease in fibrinolytic activity. The risk for PE is highest in the third trimester and in the postpartum period. This patient has risk factors for PE, including her pregnancy and recent travel, but also has other reasons for her symptoms, including the normal dyspnea of pregnancy and perhaps the recent exercise routine as a cause for the atypical chest pain, so a D-dimer level would be an appropriate next step in her evaluation.

Dyspnea is normal during pregnancy and is due to multiple factors, including progesterone-induced hyperventilation, the normal dilutional anemia of pregnancy, as well as mechanical causes as pregnancy progresses. Tidal volume increases significantly during pregnancy, most likely due to a direct progesterone-mediated increase in central respiratory drive and enhancement of the hypercapnic ventilatory drive, as well as an increase in metabolic rate and CO2 production. Some studies suggest a synergistic estrogen effect as well. There is little or no change in respiratory rate during pregnancy, and tachypnea is an unusual finding. Because of the increase in tidal volume, there is a significant increase in resting minute ventilation, and this usually occurs early in pregnancy, with a further increase at term. It is sometimes difficult to sort out normal dyspnea from pathologic dyspnea during pregnancy, since the sensation of dyspnea begins long before the mechanical effects of the enlarging uterus.

Given a possible concern for PE, one could consider further evaluation, but a 2019 study examined this question and that suggested algorithm is now being put into practice at many centers in Europe and in the United States. On the basis of this study, a D-dimer level would be the next best step in the evaluation. The YEARS study in pregnancy was a prospective study of pregnant women with suspected PE. The study examined 510 women and assessed three criteria from the YEARS algorithm, including signs of DVT, hemoptysis, and PE as the most likely diagnosis and measured the D-dimer level. In the study, PE was ruled out (and a CT pulmonary angiography study not performed) if none of the three criteria were met and the D-dimer level was <1,000 ng/mL or if one or more of the three criteria were met and the D-dimer level was <500 ng/mL. In the study, pregnant women with symptoms of DVT underwent compression ultrasound studies and were treated accordingly. In those not fitting into the described categories (ie, PE not ruled out), CT pulmonary angiography was performed. The primary outcome of the study was the incidence of VTE at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to rule out PE safely. Of the 510 women screened 12 (2.4%) were excluded. PE was diagnosed in 20 patients (4.0%) at baseline, and DVT was diagnosed in one patient (0.21%; 95% CI, 0.04%-1.2%); no patient had PE during follow-up. CT pulmonary angiography was avoided in 195 patients (39%; 95% CI, 35%-44%). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester, and CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester (our patient) and in 32% who began the study in the third trimester.

Our patient has a score of 0-1, and a D-dimer level could be helpful; in fact it came back at 250 ng/mL. Lower extremity Doppler studies would be indicated for evidence of a DVT, not present in our patient, or as part of the next step in other algorithms if the D-dimer was elevated (≥500 µg/L in one prospective study) and the probability assessment for PE was low to intermediate. In addition, clinicians often have a low threshold for ordering Doppler studies whenever VTE is suspected, since they are quick and easy to obtain. A ventilation/perfusion scan is often suggested as an initial test for suspected PE in pregnancy and is still used at some centers, although many proceed to CT pulmonary angiography, but neither would be indicated as the next study according to the YEARS algorithm. Empiric anticoagulation would not be appropriate without additional testing. Previously, D-dimer testing was not used in pregnancy because levels are often markedly elevated normally in pregnancy but also sometimes falsely low. Although D-dimer testing is now becoming part of the algorithm for evaluating PE in pregnancy with a goal to avoid radiation and unnecessary testing in low-risk patients, it is important to emphasize that D-dimer testing should not be used to exclude PE sufficiently when PE is clinically highly likely.

  • prophylactic anticoagulation prior to subsequent pregnancies
  • use either LMWH or unfractionated heparin
  • DOAC has not been studied

Source

Pregnancy, including the postpartum period, is a known risk factor for VTE, including DVT and PE. This patient has had a VTE event in a previous pregnancy, with the only transient risk factor being the pregnancy, on the basis of the subsequent negative hypercoagulable evaluation result, and the guidelines from multiple societies recommend that antepartum prophylactic anticoagulation should be initiated for subsequent pregnancies (choice D is correct). Therapeutic anticoagulation is not recommended for this indication alone (choices A and B are incorrect).

The incidence of VTE is increased throughout all trimesters of pregnancy, and investigators in some, but not all, studies suggest the risk increases progressively over each trimester, but it is well documented that the risk of VTE is highest during the postpartum period. The reasons for the increased incidence of VTE are threefold, including stasis of the lower extremities because of compression by the uterus on the inferior vena cava; endothelial damage as can occur with delivery, cesarean section, and/or abortion; and hypercoagulability due to multiple changes in coagulation factors. These latter include increases in factors V, VII, VIII, IX, X, and XII; von Willebrand factor and plasma fibrinogen; decreased protein S; increased activated protein C resistance; and an increase in plasminogen activator inhibitors. A history of VTE increases the risk of antepartum VTE from 0.6 of every 1,000 deliveries to 4.2% (95% CI, 0.3%-6.0%). In studies in which women with a history of VTE received low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) prophylaxis, the risk of antepartum VTE was reduced to 0.9% (95% CI, 0.5%-1.8%). Thus, guidelines recommend antepartum thromboprophylaxis (prophylactic low dose or intermediate dose) over no anticoagulant prophylaxis for women with a history of a pregnancy-related VTE (grade 2C). In addition, thromboprophylaxis (prophylactic low dose or intermediate dose) would be indicated in patients with a history of a VTE that was associated with another hormonal risk factor (such as estrogen or oral contraceptive related); those with a history of a single idiopathic, unprovoked VTE; and in those with a history of multiple VTEs, regardless of the cause (grade 2C). The use of low-dose LMWH vs intermediate-dose LMWH for prevention in those with a history of VTE was studied in an open-label, multicenter, randomized controlled trial. The study results showed that the intermediate dose was not associated with a lower risk of VTE recurrence, so low-dose LMWH is generally the preferred regimen. In women with a history of previous VTE associated with a nonhormonal, temporary provoking risk factor, such as trauma, immobility, surgery, and no additional risk factors, the guidelines recommend against antepartum prophylaxis (grade 2C). Observing for the development of VTE, over no form of thromboprophylaxis, would not be appropriate (choice C is incorrect). Full-dose anticoagulation compared with other regimens for this scenario has not been well studied because of concerns for bleeding risks. 

The drug of choice in pregnancy for both thromboprophylaxis and for therapeutic anticoagulation is subcutaneous LMWH over IV or subcutaneous UFH (grade 1B). The duration of thromboprophylaxis should be throughout the pregnancy and generally for at least 6 weeks after delivery (grade 2B). LMWH is preferred over UFH because of convenience and reliability and lower risks of osteoporosis, osteopenia, and thrombocytopenia. Vitamin K antagonists should not be used antepartum because of teratogenicity, particularly in early pregnancy, but can be used during lactation. The oral direct thrombin inhibitors (eg, dabigatran) or anti-Xa inhibitors (eg, rivaroxaban, apixaban) are not as well studied and should not be used during pregnancy or lactation (grade 1C). There are some data regarding the use of fondaparinux in pregnancy or during lactation, and it can be used in cases of heparin allergy or heparin-induced thrombocytopenia.1

Despite the availability of newer anticoagulants, heparin remains the cornerstone of therapy, in both unfractionated and low-molecular-weight forms, because these preparations do not cross the placenta significantly and have a robust record of safety when used in pregnant patients. Low-molecular-weight heparins (eg, enoxaparin, dalteparin, and tinzaparin) are preferred over unfractionated heparin in the outpatient setting because of their more reliable pharmacokinetics and the need for fewer daily injections (choice D is correct). In addition, the osteoporotic impact of low-molecular-weight heparins is less pronounced than that of unfractionated heparin. The duration of anticoagulation when venous thromboembolism is diagnosed during pregnancy should be individualized but usually consists of at least a 3to 6-month course that continues for at least 6 weeks postpartum.

Footnotes

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