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VTE is one of the leading etiologies of maternal morbidity and mortality, which is potentially preventable.
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Rates of VTE during pregnancy and postpartum have not decreased over the past two decades.
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CTPA is the preferred diagnostic modality for suspected PE, especially with modern low-dose techniques further reducing the radiation exposure.
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Management of DVT is primarily with anticoagulation, while the management of PE depends on the risk stratification algorithm, ranging from anticoagulation to advanced therapies
Abstract
Venous thromboembolism (VTE) is one of the leading causes of maternal mortality. Rates of VTE during pregnancy and the postpartum period have not decreased over the past two decades and pregnancyassociated VTE continues to pose a significant health challenge. Pregnant and postpartum women are at a higher risk for VTE owing to many factors. There are hormonally mediated and pregnancy-specific alterations of coagulation that favor thrombosis, including increased production of clotting factors. There are physiologic and anatomic mechanisms that also contribute, including a decreased rate of venous blood flow from the lower extemities as pregnancy progresses. Cesarean delivery also introduces VTE risk. In addition, studies have demonstrated that pregnancy-associated complications such as pre-eclampsia or peri-partum infections are associated with increased VTE rates. In this review, we discuss the recent epidemiological studies, pathogenesis, risk factors and clinical presentation as well as therapeutic options for VTE during pregnancy and the postpartum period. We also provide proposed diagnostic algorithms for diagnosis and management of VTE during pregnancy and the postpartum period based on updated evidence. Finally, we highlight knowledge gaps to guide future research.
GBD 2015 Maternal Mortality Collaborators Global, regional, and national levels of maternal mortality, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
). Venous thromboembolism (VTE), (i.e., deep venous thrombosis [DVT] and/or pulmonary embolism [PE]), is one of the leading cardiovascular etiologies of maternal morbidity and mortality (
). Pregnancy-related VTE can have serious short-term consequences as well as long-term complications including post-thrombotic syndrome, which in turn might impact the quality of life of the mother (
Prevalence and predictors for post-thrombotic syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based, cross-sectional, case-control study.
). In this review, we provide an overview for the epidemiology, mechanisms, risk factors, presentation, and management of VTE during pregnancy and postpartum period. We also highlight some potential preventative strategies. Another focus of this review is to explore the knowledge gaps in the field and provide some directions for future research.
2. Epidemiology of VTE during the pregnancy and postpartum period
The risk of VTE among pregnant and postpartum women is ∼ 6 times higher (absolute risk up to 12.2 per 10,000) compared with non-pregnant women (absolute risk 2 per 10,000) (
). The risk also increases with gestational age. The risk is about 2-fold higher during the first and second trimesters, increases up to 9-fold higher during the third trimester, while the risk is highest during the postpartum period (
). An analysis of the National Inpatient Sample (NIS) database (a US administrative database) including >50 million pregnancy and postpartum hospitalizations from 1998–2009 showed that the rates of PE increased approximately 72% during admissions for delivery (0.81 to 1.39 per 10,000 delivery hospitalizations) and 169% during postpartum hospitalizations (1.33 to 3.57 per 10,000 delivery hospitalizations) (
). This increase was not solely attributed to the rising incidence of PE alone, but also due to the more widespread utilization of computed tomographic pulmonary angiography (CTPA) among pregnant and postpartum women (
). In contrast, a recent NIS study of > 37 million pregnancy and postpartum-hospitalizations from 2007–15 showed that the rates of acute PE per 100,000 pregnancy-related hospitalizations did not change significantly during the study period (18.0 per 100,000 in 2007 versus 19.4 per 100,000 in 2015, p trends=0.22) (
). A population-based study of ∼ 1 million women, comparing the incidence of first VTE in pregnant and non-pregnant women, showed that the rate of VTE among non-pregnant women of child-bearing age was 20 per 100,000 person years (95% confidence interval [CI] 19–21), while during the antepartum period was 65 per 100,000 person years (95% CI 52–79) and during the postpartum period was 228 per 100,000 person years (95% CI 189–273) (
Some data suggest that there are some racial disparities in the rates of VTE during pregnancy and postpartum period, with Black women having the highest rates. An analysis of the NIS database years 2000–2001 constituting >9 million pregnancy and postpartum admissions revealed that Black women had the highest rate of VTE events (2.64 per 1000 deliveries), followed by White women (1.75 per 1000 deliveries) and then Hispanic women (1.25 per 1000 deliveries) (
). Similarly, another recent NIS study from 2007–2015 identified that Black race was an independent predictor of PE during pregnancy and the postpartum period (odds ratio [OR] 1.55, 95% CI 1.34–1.79) (
3. Pathogenesis of VTE during pregnancy and the postpartum period
Pregnancy and the postpartum period (i.e., defined in most studies up to 6 weeks and in others up to 12 weeks after delivery) is considered a prothrombotic state. This enhanced thrombogenicity occurs secondary to the physiological changes during pregnancy, and serves as an evolutionary protective mechanism against bleeding during childbirth. There is a physiological activation of the coagulation cascade, including the increased production of clotting factors, decreased availability of free protein S, and decreased fibrinolytic factors, resulting in a state of hypercoagulability (
Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis.
Trombofilia in gravidanza: evidenze clinico-sperimentali di uno stato trombofilico [Hypercoagulability during pregnancy: evidences for a thrombophilic state].
Besides the hormonal-mediated changes in the clotting cascade, there are other physiological and anatomical mechanisms that play a role in the increased risk of thrombotic events during pregnancy and the postpartum period. These include increased venous capacitance and venous pooling with resultant stasis, as well as mechanical obstruction by the uterus that could cause anatomic compression of the left iliac vein (
Apart from the unique predisposing pregnancy-related mechanisms for VTE, risk factors could broadly be classified into pre-existing risk factors and pregnancy-specific risk factors (Table 1). Importantly, the prevalence of most of the pre-existing risk factors are less common among pregnant and postpartum women compared with non-pregnant women (
Clinical Characteristics and Outcomes of Women Presenting with Venous Thromboembolism during Pregnancy and Postpartum Period: Findings from the RIETE Registry.
). An analysis of the RIETE (Registro Informatizado Enfermedad Trombo Embólica) registry including 596 pregnant and 523 postpartum women with confirmed VTE, compared with 8,084 women <50 years, showed that the prevalence of pre-existing risk factors including recent immobilization, active cancer or recent travel was lower among pregnant and postpartum women with VTE compared with VTE in non-pregnant women (19% vs 60%). Pregnant- and postpartum women also had lower prevalence of associated comorbidities including older age, obesity, hypertension and smoking. Although the prevalence of thrombophilia was higher among pregnant and postpartum women, it should be noted that markers such as D-dimer are normally elevated during pregnancy and the postpartum period (
Clinical Characteristics and Outcomes of Women Presenting with Venous Thromboembolism during Pregnancy and Postpartum Period: Findings from the RIETE Registry.
There are a number of pre-existing risk factors that independently increase the risk of VTE including older age, obesity, prior VTE, thrombophilia, immobilization, recent travel, active cancer and smoking (
Clinical Characteristics and Outcomes of Women Presenting with Venous Thromboembolism during Pregnancy and Postpartum Period: Findings from the RIETE Registry.
). In a nested case-control study of > 70,000 Danish women, obesity, defined as BMI > 30 kg/m2, was associated with an increased risk of VTE in pregnancy and postpartum after adjustment for other risk factors (adjusted OR 5.3, 95% CI 2.1–13.5), which was driven by a higher risk of PE (adjusted OR 14.9, 95% CI 3.0-74.8) rather than DVT (adjusted OR 4.4, 95%CI 1.6–11.9) (
). In a recent NIS analysis including > 37 million pregnancy and postpartum-hospitalizations, hypertension (OR 2.14, 95% CI 1.62–2.84) and smoking (OR 2.38, 95% CI 1.94–2.92) were independently associated with pregnancy- and postpartum-related PE (
Prior VTE is a strong risk factor for VTE in pregnancy and postpartum period. While approximately 15-25% of thromboembolic events in pregnancy are recurrent events, the risk of recurrent VTE in pregnancy is increased up to 4-fold (
). Women with prior exogenous estrogen-associated VTE have the highest risk of VTE in antepartum period without prophylactic anticoagulation (6.4%,95% CI 3.9%–10.4%), followed by those with prior unprovoked VTE (3.6%, 95% CI 1.4%–8.9%) and prior provoked VTE (1.0%, 95% CI 1.9%–5.7%) (
Inherited thrombophilia is one of the most important contributors to the heightened risk of VTEs, and the risk among pregnant women is ∼ 15-fold higher compared with non-pregnant women (OR 15.4, 95% CI 10.8–22.0) (
). In a systemic review of 79 studies, the inherited thrombophilias among pregnant women associated with the highest risk of VTE were homozygous Factor V Leiden (FVL) (OR 34.4, 95% CI 9.9–120.1), homozygous prothrombin G20210A gene variant (PT) (OR 26.4, 95% CI 1.2–559.3), heterozygous FVL (OR 8.3, 95% CI 5.4–12.7), and heterozygous PT G20210A gene variant (OR 6.8,95% CI 2.5–18.8) (
). In a Norwegian case-control study of 613,232 pregnancies, an emergency cesarean delivery was associated with a higher risk of VTE (OR 4.0, 95% CI 3.0–5.3) than a planned surgical delivery (OR 2.7, 95% CI 1.8–4.0) (
). A Scottish registry of > 1.4 million maternity hospitalizations also showed that the probability of suffering from a DVT after an emergent cesarean delivery was 2.1 times higher than after vaginal delivery (incidence rate ratio [IRR] 2.06, 95% CI 1.63–2.61), compared with only a 1.4‐fold increase compared with elective procedure (IRR 1.39, 95% CI 1.0–1.94) (
). Cesarean delivery is associated with activation of the coagulation cascade as well as uteroplacental surface alterations which increase the risk of thrombogenicity (
). In a study of >18,000 IVF pregnancies from 1995–2005, VTE incidence rate was 28.6 per 10,000 pregnancy-years (95% CI 20.6–39.6) compared with 10.7 per 10,000 women-years in non-IVF reference pregnancies (
). Multiple IVF pregnancies were associated with higher rates of VTE (IRR 4.4, 95% CI 2.4-8.3) than singleton IVF pregnancies (IRR 2.8, 95% CI 1.9-4.1) (
). In an analysis of the RIETE registry including > 6,700 women of child-bearing age with VTE, 41 (0.6%) had a thromboembolic event that was related to IVF, and PE was significantly more frequent among women with unsuccessful IVF (OR 5.0, 95% CI 1.2–20.7) (
). In one large study of 23,498 women who gave birth after IVF and 116,960 women with natural pregnancies matched based on age and calendar year, the risk of pregnancy-associated VTE was higher among those who underwent IVF, after adjusting for the differences in baseline characteristics and other risk factors (
). The underlying pathogenesis for VTE in the setting of an IVF pregnancy has been linked to the estrogen surge. During IVF, the controlled ovarian stimulation leads to multiple oocytes and supra-physiological levels of estrogens, resulting in a pro-coagulant like state which increases the risk of VTE (
). In an analysis of >1 million maternity discharges from the Scottish Morbidity Record registry, pre-eclampsia was associated with a higher risk of VTE in the postpartum period by 1.6‐fold (IRR 1.6; 95% CI 1.01–2.53) compared with uncomplicated pregnancies (
). In a case-control study of 608 women with pregnancy-associated VTE and 114,940 thrombosis-free pregnant women, pre-eclampsia was associated with a 3-fold risk of VTE during the postpartum period (OR 3.0, 95%CI 2.0–4.4), but not before delivery (OR 0.8, 95% CI 0.4–1.6) (
). Although the mechanisms underlying this increased thrombosis risk remain to be fully elucidated, pre-eclampsia is linked with the altered expression of placental anti-angiogenic factors which induces endothelial dysfunction, resulting in proteinuria and hypertension (
). The increased expression of procoagulant factors, attenuation of endogenous anticoagulant activity, and increased platelet activity have all been implicated in the prothrombotic tendency (
Infections are another recognized trigger for VTE during pregnancy and the postpartum period. In a study of 39,285 women undergoing cesarean delivery, intrapartum chorioamnionitis was associated with an increased risk for DVT (RR 2.52, 95% CI 1.23–5.16) and PE (RR 2.46, 95% CI 1.10–5.54) (
). Similar findings were replicated in a study of NIS database, that included > 9 million pregnant and > 73,000 postpartum women, showing that postpartum infections were associated with a higher incidence of VTE (OR 4.1, 95% CI 2.9–5.7) (
Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis.
). A population-based cohort study of >280,000 women from the United Kingdom showed that urinary tract infection was associated with 88% increased risk of VTE during the antepartum period (adjusted RR 1.88, 95% CI 1.28–2.77) (
). There have been some proposed pathophysiological pathways for the association between infections and thrombosis. Infections activate the inflammatory cascade that causes a surge in the levels of pro-inflammatory cytokines. There is activation of coagulation cascade with platelet activation and aggregation, increased oxidative stress, and impaired endothelial function, ultimately increasing the risk for thrombosis (
The symptoms and signs of VTE are oftentimes non-specific, and might overlap with physiological changes of pregnancy including dyspnea, lower extremity edema, and tachycardia. Therefore, there is a potential of misdiagnosing VTE during pregnancy and the post-partum period. This dilemma is reflected by studies that revealed a prevalence of PE <5% among pregnant women in whom PE is suspected, as compared with a rate of 15 to 20% among non-pregnant women (
). While there are many scoring systems to assess for the risk of VTE clinically among non-pregnant women, it is important to note that studies validating these scoring systems did not include pregnant and postpartum women thus might not be extrapolated in this population (
Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.
Christopher Study Investigators Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography.
). D-dimer levels are increased in pregnancy compared with non-pregnant patients, and continue to increase throughout pregnancy, limiting the diagnostic value when considering the likelihood of VTE (
). However, normal D-dimer levels can be a simple, non-invasive and inexpensive way of ruling out VTE during pregnancy when there is low-to-intermediate clinical pretest probability, while high D-dimer levels warrant further investigation, similar to non-pregnant women (
) (Fig. 2). A recent study, examining the use of D-dimer in combination with a developed algorithm involving clinical signs of DVT and PE showed that PE was safely ruled out in 498 pregnant women with suspected PE, sparing 32% to 65% from undergoing a computed tomography pulmonary angiogram (CTPA), thereby reducing the radiation exposure to the fetus (
Diagnostic algorithm that could be adopted during pregnancy and postpartum when there are signs and symptoms that raise suspicion for VTE, including unilateral extremity swelling, dyspnea and/or hypoxia.
The diagnosis of symptomatic DVT is established by lower extremity duplex ultrasonography (DUS), which is widely available and does not carry the risk of radiation to the fetus. The finding of DVT on DUS not only establishes the diagnosis of DVT, but also circumvents the need for additional chest imaging if PE is clinically suspected, as the upfront management would be the same. However, if PE is clinically suspected and DUS does not document DVT, additional diagnostic testing to assess for PE is required via chest imaging using CTPA and/or lung perfusion scintigraphy (V/Q scan) (
The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
). Compared with general population in which 80% of DVTs are located in the calf, the majority of DVTs in pregnancy are located proximally; 62% of DVTs affect iliofemoral veins, followed by iliac vein (17%), and only 6% occur in the calf veins (
). In a study of 54 pregnant and postpartum women with ultrasound-confirmed DVT, pregnant women were more likely to have a left-sided DVT (76% vs 47%) compared with postpartum women (
). The detection of DVT in iliofemoral veins using compression ultrasonography is usually low yield, given incompressibility of the veins because of their intrapelvic location as well as pregnancy-related altered blood flow mechanics and compressibility in the proximal veins (
Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging.
). A study including 221 symptomatic pregnant women evaluated the strategy of daily serial venous duplex ultrasonography over 7 consecutive days to improve diagnostic accuracy (
Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging.
). While the strategy reliably excluded DVT in symptomatic pregnant women, the fact that women who were confirmed to have DVT were all diagnosed on the initial duplex examination suggests that duplex ultrasound has adequate sensitivity even in pregnant women.
PE most commonly manifests as dyspnea. Importantly, two-thirds of pregnant and postpartum women have normal oxygen saturation on presentation, and therefore absence of hypoxia should not rule out PE (
Clinical Characteristics and Outcomes of Women Presenting with Venous Thromboembolism during Pregnancy and Postpartum Period: Findings from the RIETE Registry.
) (Table 2). In general, CTPA and V/Q scan are two commonly used imaging modalities for detection/exclusion of PE in pregnant women. Although there has not been any direct comparison of CTPA and V/Q scan, both have their advantages and disadvantages. In a systematic review of 11 studies (695 CTPA and 665 V/Q scans) evaluating both modalities for diagnosing PE during pregnancy, CTPA showed a sensitivity of 80% and a 100% negative predictive value. By contrast, V/Q scan, had a 100% sensitivity as well as 100% negative predictive value (
). Although CTPA is associated with slightly more radiation exposure (∼3-10 mSv) compared with V/Q scan (∼2 mSv), it is more easily accessible and widely available around the clock in most centers and has less interobserver and technique variability with a shorter acquisition time (
). Additionally, modern low-dose CTPA can help reduce the maternal radiation exposure to <1 mSv without compromising the image quality, making CTPA a reasonable test to exclude PE in pregnancy (
Low dose computed tomography pulmonary angiography protocol for imaging pregnant patients: Can dose reduction be achieved without reducing image quality?.
). The emergence of more sophisticated modern imaging techniques has further lowered the maternal and fetal radiation exposure, and hence the risk associated with it (
). Chest magnetic resonance imaging is another modality that can be used in the diagnostic armamentarium of PE, which has the advantage of being radiation free; however, the limited availability and unknown maternal and fetal safety data in humans are major limitations (
The mainstay of treatment for acute VTE in pregnancy and postpartum is anticoagulation. The anticoagulation of choice is heparin, preferably low molecular weight heparin (LMWH) although unfractionated heparin (UFH) can also be used, since both agents do not cross the placental barrier (
). This is in contrast to coumarin derivatives, such as warfarin, that cross the placenta and have the potential to cause teratogenicity, pregnancy loss, fetal bleeding, and neurodevelopmental deficits (
). Similarly, the direct-acting oral anticoagulants (DOACs) cross the placenta, and since their reproductive effects in humans are unknown, they are not recommended during pregnancy (
). The preference of LMWH over UFH is based on extrapolation of efficacy data from trials in the non-pregnant population where LMWH is more effective, has more predictable pharmacokinetics and a more favorable risk profile than UFH (
Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.
Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials.
). The recommendations for dosing regimen of LMWH also originate from the non-pregnant population, given the paucity of data in pregnant patients. A systemic review of 5 studies, comprising of >1,500 non-pregnant patients, demonstrated no difference in the risk of recurrent VTE or bleeding when once daily dose was compared with twice daily dosing of LMWH (
). Small observational studies in pregnant women have also shown no difference in in recurrent VTE and bleeding when comparing single- versus twice-daily dosing of LMWH (
British Society for Haematology Obstetric Haematology Group. The management of antenatal venous thromboembolism in the UK and Ireland: a prospective multicentre observational survey.
). With the progression of pregnancy, dose adjustment might be necessary given the change in maternal weight to ensure adequate anticoagulation. While pregnant women on LMWH often have subtherapeutic trough anti-Xa levels and require higher doses to reach the target levels, routine monitoring of anti-Xa levels is not recommended given the predictable profile of LMWH and the assay for anti-Xa level has some limitations (
Ni Áinle F. Adjustment of therapeutic LMWH to achieve specific target anti-FXa activity does not affect outcomes in pregnant patients with venous thromboembolism.
). Fondaparinux is another indirect inhibitor of Factor Xa, but the data on its use in pregnancy is limited. Fondaparinux is not considered as a first-line anticoagulant since it might cross the placental barrier in small amount, however; it could be cautiously used as an alternative option in patients with heparin-induced thrombocytopenia (
The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
Closer to delivery, twice-daily LMWH dosing or, preferably, switching to UFH may be considered in light of the shorter half-life, reducing risk of maternal bleeding and ensuring access to neuraxial analgesia and anesthesia (
). Epidural catheter placement is generally recommended after at least a 24-hour interval between the last dose of greater-than-prophylactic-dose LMWH (
). If the patient is on UFH, UFH should be stopped 4 to 6 h before delivery or anticipated need for epidural insertion to allow for normalization of partial thromboplastin time (
). Post-delivery, in the absence of concern for bleeding, therapeutic LMWH or UFH can be restarted 24 hours after epidural catheter removal, 6 to 12 h after a vaginal delivery, or 12 to 24 h after Cesarean section (
Councils of the Society of Obstetric Medicine of Australia and New Zealand; Australasian Society of Thrombosis and Haemostasis Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period.
). Although no studies have assessed the optimal duration of anticoagulant therapy for treatment of pregnancy-related VTE, anticoagulation therapy is recommended for the remainder of the pregnancy and for at least 6 weeks after delivery and until at least 3 months of treatment has been given in total (
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
While the mainstay of treatment for acute DVT is anticoagulation, the role of catheter-directed thrombolysis, which is a minimally invasive technique for the treatment of acute ilio-femoral DVT with potential to prevent post-thrombotic syndrome, is not well established in pregnant women. The primary concern with performing catheter-directed thrombolysis is the fetal radiation exposure, particularly during the first trimester due to the high radiation dose (
). In the second and third trimesters, however, appropriate precautions including shielding and dose reduction techniques could make this procedure safer (
). In cases of severe venous outflow obstruction after thrombolysis, iliac vein stent placement could be delayed until after delivery if possible. A study of 11 pregnant women who underwent catheter-directed thrombolysis for acute symptomatic iliofemoral DVT showed that >90% clot lysis was achieved in 9 patients, with 8 patients requiring stent deployment, and none developed post-thrombotic syndrome during a median of 20-month follow up(
). Two patients presented in the first trimester and the pregnancy was terminated after thrombolysis, 2 patients presented in third trimester and thrombolysis was delayed until after delivery while 7 patients with postpartum DVT underwent immediate catheter-directed thrombolysis.
6.2 Management of PE
The management of acute PE in pregnancy involves initial risk stratification and clinical evaluation including hemodynamic status and right ventricular size and function, in conjunction with imaging, biomarker studies and the use of validated scoring systems to stratify the severity of PE (
The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
). Shared decision making through a multidisciplinary team of obstetrics, cardiology, pulmonology, hematology, vascular medicine, anesthesiology/intensive care, cardiothoracic surgery, and interventional radiology is important. Although the data on the treatment of acute PE in the pregnant population is sparse, there are some guideline recommendations to help manage these patients.
For acute low-risk PE, defined as hemodynamically stable with normal right ventricular function and absence of end-organ damage, the preferable choice is LMWH, while the other option is UFH (
The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
). Acute high-risk PE, characterized by hemodynamic instability with end-organ hypoperfusion, is rare during pregnancy but potentially life-threatening and requires hospitalization (
The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
). Case reports and series suggest that advanced therapies including systemic and catheter-based thrombolysis, as well as surgical embolectomy could be performed in high-risk PE patients during all three trimesters as well as in the postpartum period (
). A systemic review of 83 pregnant women treated with systemic thrombolysis for severe PE, including ∼80% massive PE, showed that 94.0% of women (78/83; 95% CI, 86–98) survived: 96.7% during pregnancy (59/61; 95% CI, 89–100) and 86.4% after delivery (19/22; 95% CI, 65–97). The risk of major bleeding was 17.5% during pregnancy and 58.3% in the postpartum period, mainly because of severe postpartum hemorrhages (
). In the absence of hemodynamic instability, patients with right ventricular strain on imaging or those with clinically severe PE including a constellation of oxygen saturation <90%, tachycardia, tachypnea and hypothermia, or multiple risk factors/comorbidities including old age, malignancy, heart failure or chronic lung disease are considered intermediate risk (Fig. 3). Patients with elevated troponin and RV dilatation and/or dysfunction are further stratified into intermediate-high risk group compared with intermediate-low risk group patients who have a normal serum troponin. While intermediate-low risk group is treated with anticoagulation alone, very close monitoring is required for patients falling in the intermediate-high risk category given the potential risk of deterioration (
The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC).
For pregnant women with an absolute contraindication to anticoagulant treatment or have recurrent PE despite adequate anticoagulation, inferior vena cava (IVC) filters could be considered with the goal to prevent additional venous clots from reaching the pulmonary circulation. Although there is limited experience with their use in pregnancy, an analysis from the RIETE registry of pregnant and postpartum women with VTE from 2001 to 2019 showed that among 34 women who received IVC filters during the pregnancy, only one woman had a complication in the form of vein perforation during filter retrieval (
Clinical Characteristics and Outcomes of Women Presenting with Venous Thromboembolism during Pregnancy and Postpartum Period: Findings from the RIETE Registry.
). A systemic review including 124 pregnant women who received an IVC filter showed that IVC filters are not only effective in preventing PE but the complications are also comparable to the general population. However, there is insufficient evidence to suggest that IVC filters should be routinely used in pregnancy in patients with DVT (
). These data can provide some reassurance with regard to the use of IVC filters during pregnancy, especially during third trimester for women who are not candidate for anticoagulation.
7. Recurrence and Prevention of VTE in pregnancy and postpartum
Patients with pregnancy associated VTE have a risk of recurrence up to 13% during subsequent pregnancies (
Recurrence of Clot in This Pregnancy Study Group. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group.
). Some evidence suggest that thromboprophylaxis is associated with a reduction in the risk of VTE recurrence. An analysis of 159 women with at least one pregnancy after a VTE showed that the probability of VTE recurrence during pregnancy without thromboprophylaxis was 6.2% (95% CI 1.6–10.9%) and the risk was constant throughout pregnancy, while no VTE recurrences were observed in those who received prophylaxis (
). Another, prospective national study of long‐term LMWH thromboprophylaxis that included 326 women with prior VTE showed a 88% relative risk reduction in VTE in the combined ante‐ and post‐partum subgroups (
Working Group on Hemostatic Disorders (Hem-ARG), Swedish Society of Obstetrics and Gynecology Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
), universal thromboprophylaxis may not be a safe approach, because of the risk for maternal bleeding, as well as the risk of heparin-induced thrombocytopenia and osteoporotic fractures associated with the administration of heparin (
). Therefore, routine thromboprophylaxis is recommended only for women considered at high risk for VTE based on certain factors such as a previous estrogen associated VTE or certain inherited thrombophilia (
American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy.
). However, there is disagreement and inconsistency regarding the characteristics of women at higher risk of developing a first VTE during pregnancy or postpartum, combined with a lack of data regarding the relative effect of those risk factors with respect to the absolute risk of VTE.
There have been no head-to-head studies comparing LMWH vs UFH in pregnant women, and the data for prophylaxis are driven from the non-pregnant population (
Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.
Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials.
). LMWH is typically administered during pregnancy at different doses (prophylactic, intermediate, therapeutic), and evidence-based consensus regarding optimal dosing strategy is lacking. For example, for enoxaparin, the prophylactic dose is 40 mg subcutaneous daily, the intermediate dose (defined as higher than prophylactic but less than therapeutic dose) is 40mg subcutaneous twice daily, while the therapeutic dose is 1 milligram per kilogram body weight twice daily. Studies comparing these dosing strategies have not demonstrated any difference in efficacy or safety between the different doses (
). While the American Society of Hematology (ASH) recommends a prophylactic dose, the American College of Chest Physicians (ACCP) and American College of Obstetricians and Gynecologists (ACOG) recommendations support the use of both prophylactic and intermediate dosing (
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy.
). A history of a single idiopathic, pregnancy-associated, or estrogen associated VTE is associated with >10-fold higher risk and >1% absolute risk of VTE (
). Data suggest that women with a prior pregnancy-associated or oral contraceptive-associated VTE are more likely to have a recurrent VTE in pregnancy than those with an unprovoked or non–hormone-associated prior VTE (
). Among pregnant women with no or 1 risk factor (excluding a known thrombophilia), antepartum and postpartum pharmacological thromboprophylaxis is not generally recommended (
). Although clinical risk factors increase the risk of antepartum and postpartum VTE above the general population risk (∼0.6 per 1000 deliveries in the each of the antepartum and postpartum time periods), the majority of individual risk factors have a low absolute VTE risk of <1%. The ASH and ACCP guidelines recommend prophylactic anticoagulation in antepartum women with either unprovoked or estrogen associated VTE and postpartum in women with any prior VTE, irrespective of the etiology (
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy.
) (Table 3). In patients with inherited thrombophilia, the candidacy for thromboprophylaxis is determined by the type of hereditary thrombophilia, family history of VTE and antepartum versus postpartum period.
Table 3Societal guidelines regarding VTE prophylaxis in pregnant women with inherited thrombophilia.
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy.
For women with antiphospholipid antibody syndrome and a history of three or more pregnancy losses, antepartum administration of prophylactic or intermediate-dose unfractionated heparin or prophylactic low-molecular-weight heparin combined with low-dose aspirin (75-100 mg/d) is recommended (
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
). A meta-analysis suggested that prophylactic use of heparin and low-dose aspirin may reduce pregnancy loss by 50% in women with recurrent pregnancy loss and antiphospholipid antibodies (
). The treatment should begin in the first trimester and continue up to 6 weeks postpartum in all patients with thrombophilia who are candidates for thromboprohylaxis.
For cesarean deliveries, emergency cesarean delivery itself qualifies for postpartum prophylaxis in some guidelines (
VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
), while others suggest pharmacological prophylaxis after caesarean section only if additional risk factors are present (such as obesity, advanced age, underlying malignancy, prolonged immobilization) (82). Early ambulation and/or mechanical devices (e.g., intermittent pneumatic compression) are suggested in those patients who undergo a cesarean delivery and do not have any additional risk factors for VTE. IVF is associated with an increased risk of VTE; however, in unselected patients, the absolute incidence of symptomatic VTE seems low at less than 1% (
Hansen AT, Kesmodel US, Juul S, Hvas AM. No evidence that assisted reproduction increases the risk of thrombosis: a Danish national cohort study. Hum Reprod. May;27:1499-503.
VTE is a potentially preventable etiology of maternal mortality. The morbidity and mortality associated with VTE remain alarming, which calls for future efforts to fill in the gaps that exist in our knowledge and understanding of the mechanisms, risk factors and management (Table 4). First, the existing VTE prediction scores are based on criteria that exclude pregnant women and rely on features that rarely apply to pregnant women, such as advanced age or cancer. Therefore, there is a need for studies aimed to devise risk scores and predictive models that could be applicable to pregnant and postpartum women. There is also a need to develop educational programs to equip healthcare providers with knowledge to identify, manage and prevent VTE in pregnant women. Second, current recommendations for thromboprophylaxis during pregnancy and postpartum are stratified based on thrombotic history or underlying thrombophilia. There are other important risk factors (e.g., age, race, BMI, infections and complications of pregnancy) that need to be factored into decision-making process regarding the prevention of pregnancy-related VTE. Third, further studies validating the diagnostic algorithms for VTE in pregnancy, using current radiological imaging techniques and low-dose radiation, are encouraged. Fourth, large scale studies are needed to assess the efficacy and safety of advanced therapeutic options for high-risk VTE, however such studies might be difficult given the rarity of this condition. Addressing these knowledge gaps will help provide physicians with better understanding of VTE, and help improve the outcomes of pregnant and postpartum women.
Table 4Knowledge gaps in VTE during pregnancy and post-partum period.
Develop and validate risk prediction models for VTE risk in pregnancy and postpartum women.
Consideration of important VTE risk factors other than prior VTE and thrombophilia in the decision-making process for thromboprophylaxis.
Assess the efficacy, and comparative analysis, of the available therapeutic options for VTE in pregnancy and postpartum
Assess the optimal duration and intensity of anticoagulation treatment for and prophylaxis of pregnancy-associated VTE
VTE is one of the leading etiologies of maternal morbidity and mortality, and is potentially preventable. There are pregnancy-mediated mechanisms that pose a greater risk of VTE in pregnant women compared with their non-pregnant counterparts, especially in the postpartum period. CTPA is the preferred diagnostic modality for suspected PE, especially with modern low-dose techniques further reducing the radiation exposure. While the management of DVT is primarily with anticoagulation, the management of PE depends on the risk stratification algorithm, ranging from anticoagulation in low risk patients to advanced therapies in patients with high risk PE. There are some indications for thromboprophylaxis. Future studies are needed to fill in some knowledge gaps in this field.
Funding
None.
Disclosures
Dr. Elgendy has disclosures unrelated to this manuscript content including receiving research grants from Caladrius Biosciences, Inc. The other authors have nothing to disclose.
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The care of pregnant persons at risk for or with known or suspected venous thromboembolism (VTE) has many challenges; including specialized content knowledge, a limited high-quality evidence base upon which to make decisions, conflicting guideline recommendations, the need to consider the wellbeing of both the mother and the fetus, and an informed and engaged patient population that appropriately embraces shared decision making. For some, these challenges are what makes this area of thrombosis medicine rewarding, while for others they provoke anxiety.
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