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Management of venous thromboembolism in pregnancy

Open AccessPublished:February 06, 2022DOI:https://doi.org/10.1016/j.thromres.2022.02.002

      Highlights

      • Venous thromboembolism (VTE) comprises a major factor of maternal mortality.
      • Critical clinical evaluation is warranted for efficient differential diagnosis between physiologic changes of pregnancy and VTE that is often challenging.
      • Anticoagulation is the cornerstone of VTE therapy but more complex therapies can be utilized for individual cases with comorbidities.

      Abstract

      Venous thromboembolism (VTE) in pregnancy, consisting of deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major factor of maternal mortality. Several patient-specific risk factors along with the physiologic changes of pregnancy promote a state of hypercoagulability in pregnant women. Detailed assessment of all pregnant women can establish a risk profile that would guide clinical decisions, and balance potential therapeutic benefits with side effects. Differentiating between physiologic changes of pregnancy and symptoms of VTE can be challenging and warrants meticulous clinical evaluation. Timely and accurate diagnosis of VTE with proper imaging is essential for its management, and systemic anticoagulation remains the cornerstone of VTE prevention and therapy. Furthermore, advanced invasive treatment options such as inferior vena cava filters and thrombectomy can be considered for complex cases. Importantly, the risk of systemic anticoagulation should be balanced against the risk of VTE-associated morbidity and mortality for mother and fetus, and an informed decision should be made. In this review, we present an up-to-date overview of VTE management in pregnancy and the postpartum period.

      Keywords

      1. Introduction

      Pregnancy and puerperium are well-established risk factors for venous thromboembolic disease (VTE) [
      • Park J.E.
      • Park Y.
      • Yuk J.S.
      Incidence of and risk factors for thromboembolism during pregnancy and postpartum: a 10-year nationwide population-based study.
      ]. During pregnancy, the risk of VTE is about 5-fold compared to non-pregnant women, and becomes 30 to 60-fold at postpartum [
      • Jackson E.
      • Curtis K.M.
      • Gaffield M.E.
      Risk of venous thromboembolism during the postpartum period: a systematic review.
      ]. Deep vein thrombosis (DVT) events are more frequent during pregnancy, while pulmonary embolism (PE) events are more likely to occur at the postpartum period [
      • Pomp E.R.
      • Lenselink A.M.
      • Rosendaal F.R.
      • Doggen C.J.
      Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study.
      ]. DVT is associated with adverse obstetric outcomes and is a significant contributor to maternal morbidity (e.g., increased frequency of post-thrombotic syndrome in pregnant women) and mortality [
      • James A.H.
      • Tapson V.F.
      • Goldhaber S.Z.
      Thrombosis during pregnancy and the postpartum period.
      ]. PE, as a result of DVT, is the leading cause of maternal mortality in the United Kingdom and Ireland, and it ranks sixth in the United States [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola V.P.
      • et al.
      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).
      ,

      Division of Reproductive Health NCfCDPaHP. Pregnancy Mortality Surveillance System.

      ]. Therefore, the effective prevention and management of VTE and its complications are crucial [
      • Ernst D.M.
      • Oporto J.I.
      • Zuniga P.A.
      • Pereira J.I.
      • Vera C.M.
      • Carvajal J.A.
      Maternal and perinatal outcomes of a venous thromboembolism high-risk cohort using a multidisciplinary treatment approach.
      ]. However, accurate VTE diagnosis in this population is inherently challenging due to the physiological changes of pregnancy and the potential risks that some of the diagnostic imaging methods may pose to the developing fetus. Therapeutics decisions should be made after thorough balancing of the risks and potential benefits of each strategy for the mother and fetus. In this review, we offer an up-to-date overview of VTE management in pregnancy and puerperium.

      2. Pathophysiology of VTE in pregnancy

      Pregnancy is associated with the gradual development of a hypercoagulable state with a physiologic increase in clotting factors such as von Willebrand factor, fibrinogen, and factors II, VII, VIII, IX, and X, from conception to delivery. Notably, fibrinogen levels rise to 50% [
      • Kidson-Gerber G.
      The Obstetric Hematology Manual2011 September 5.
      ]. These physiological changes, while aiming to facilitate hemostasis after delivery, affect prothrombin time (PT) and partial thromboplastin time (PTT), and could complicate the anticoagulation monitoring of pregnant women. The hyperestrogenic state of pregnancy leads to decreased activity of protein S, which normally interacts with protein C to inactivate Factors Va and VIIIa directly, via decreased production, and indirectly via increasing C4b binding protein [
      • Castoldi E.
      • Hackeng T.M.
      Regulation of coagulation by protein S.
      ,
      • Malm J.
      • Laurell M.
      • Dahlback B.
      Changes in the plasma levels of vitamin K-dependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception.
      ]. Furthermore, increased levels and activity of thrombin-activated fibrinolysis inhibitor, plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2 inhibit fibrinolysis. The three most important factors leading to venous stasis and venous hypertension during pregnancy parturition and puerperium are: (i) decreased venous tone mediated by endothelial mediators such as nitric oxide that is upregulated by estradiol and vasodilatory prostaglandins such as PGI2, (ii) compression of inferior vena cava and iliac veins by the gravid uterus and, (iii) endothelial injury to pelvic veins during delivery [
      • James A.H.
      Thrombosis in pregnancy and maternal outcomes.
      ,
      • Soma-Pillay P.
      • Nelson-Piercy C.
      • Tolppanen H.
      • Mebazaa A.
      Physiological changes in pregnancy.
      ].

      3. Risk factors for VTE in pregnancy

      Pregnant women exhibit a 2-fold higher risk for VTE in the first two trimesters and progress to a 9-fold higher risk in the early postpartum period compared to non-pregnant women [
      • Pomp E.R.
      • Lenselink A.M.
      • Rosendaal F.R.
      • Doggen C.J.
      Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study.
      ,
      • Parunov L.A.
      • Soshitova N.P.
      • Ovanesov M.V.
      • Panteleev M.A.
      • Serebriyskiy I.I.
      Epidemiology of venous thromboembolism (VTE) associated with pregnancy.
      ]. Most postpartum VTE cases are attributed to thrombophilia and Cesarean section delivery [
      • Nichols K.M.
      • Henkin S.
      • Creager M.A.
      Venous thromboembolism associated with pregnancy: JACC focus seminar.
      ]. Preeclampsia is another factor that increases the risk for postpartum VTE [
      • Rodger M.
      Pregnancy and venous thromboembolism: 'TIPPS' for risk stratification.
      ]. Pregnant women with a personal past medical history of VTE are at higher risk for developing pregnancy-associated VTE. Therefore, it is recommended that women with a history of both provoked or unprovoked VTE or first-degree relatives who have a history of inherited thrombophilia should be evaluated for antiphospholipid syndrome and other inherited thrombophilias including factor V Leiden (FVL) and prothrombin G20210A gene variant (PT G20210A), as well as antithrombin III, protein C, and protein S deficiencies. The population identified as high risk (history of VTE, thrombophilia) should receive a prophylactic or intermediate dose of low molecular weight heparin (LMWH) or unfractionated heparin (UFH) antepartum and postpartum [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ]. Women with recurrent pregnancy loss or stillbirth should be tested for antiphospholipid syndrome, which increases the risk of pregnancy-associated VTE by 5%–12% [
      • Lima F.
      • Khamashta M.A.
      • Buchanan N.M.
      • Kerslake S.
      • Hunt B.J.
      • Hughes G.R.
      A study of sixty pregnancies in patients with the antiphospholipid syndrome.
      ,
      • Committee on Practice Bulletins-Obstetrics ACoO
      Gynecologists. Practice bulletin no. 132: Antiphospholipid syndrome.
      ]. Assisted reproduction methods elevate VTE risk by 2- to 3-fold during the first trimester, due to exposure to high estradiol levels [
      • Sennstrom M.
      • Rova K.
      • Hellgren M.
      • Hjertberg R.
      • Nord E.
      • Thurn L.
      • et al.
      Thromboembolism and in vitro fertilization - a systematic review.
      ]. Other risk factors for pregnancy-related VTE include maternal age >35, nulliparity, multiple gestations, gestational diabetes, antepartum hemorrhage, hypertension, smoking and obesity [
      • Nichols K.M.
      • Henkin S.
      • Creager M.A.
      Venous thromboembolism associated with pregnancy: JACC focus seminar.
      ].

      4. Diagnosis of DVT in pregnancy

      Timely and accurate diagnosis of DVT in pregnancy is imperative because if left untreated it can progress to PE, which can be detrimental for mother and fetus. DVT is more common in pregnant women as compared to non-pregnant women. Nonetheless, contrary to the general population where DVT originates mostly in the calf and progresses proximally, in pregnant women DVT arises mostly from the proximal veins of the left lower limb (79% from iliofemoral veins) [
      • McLean K.
      • Cushman M.
      Venous thromboembolism and stroke in pregnancy.
      ,
      • Chan W.S.
      • Spencer F.A.
      • Ginsberg J.S.
      Anatomic distribution of deep vein thrombosis in pregnancy.
      ]. DVT diagnosis can be challenging as some of its clinical manifestations (i.e. lower extremity edema, pelvic and back pain) mimic pregnancy-associated symptoms. Well-established clinical prediction tools for DVT in the general population, such as Wells' criteria and modified Geneva score have limited use in pregnant women [
      • Cohen S.L.
      • Feizullayeva C.
      • McCandlish J.A.
      • Sanelli P.C.
      • McGinn T.
      • Brenner B.
      • et al.
      Comparison of international societal guidelines for the diagnosis of suspected pulmonary embolism during pregnancy.
      ,
      • Hendriksen J.M.T.
      • Geersing G.-J.
      • Lucassen W.A.M.
      • Erkens P.M.G.
      • Stoffers H.E.J.H.
      • van Weert H.C.P.M.
      • et al.
      Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care.
      ]. A clinical prediction tool for pregnant women in the first trimester has been proposed by Chan et al. to facilitate DVT diagnosis. It includes three clinical parameters: (i) left lower extremity symptoms, (ii) difference in calf circumference of more than 2 cm and (iii) presentation in the first trimester, collectively called the LEFt rule. The LEFt rule can be used in cases where the initial diagnostic work-up with compressive ultrasound (CUS) is equivocal [
      • Chan W.S.
      • Lee A.
      • Spencer F.A.
      • Crowther M.
      • Rodger M.
      • Ramsay T.
      • et al.
      Predicting deep venous thrombosis in pregnancy: out in "LEFt" field?.
      ]. The use of D-dimers to guide diagnostic decisions in pregnancy is limited due to their physiologic increase during pregnancy, especially during second and third trimesters [
      • Eichinger S.
      D-dimer testing in pregnancy.
      ]. The sensitivity of D-dimers varies according to threshold from 94% (cut-off 500 ng/ml) to 90% (cut-off 1000 ng/ml). Nonetheless, testing of serial levels of red blood cell agglutination D-dimer, a method for high-sensitive D-dimer testing, has been evaluated in the SimpliRED prospective cohort study as a diagnostic tool to exclude DVT in pregnancy. This method is known as high-sensitive D-dimer testing. SimpliRed had a high negative predictive value, which according to Chen et al. could reach 100% (81 of 81 patients) for the exclusion of DVT in pregnant women [
      • Chan W.S.
      • Chunilal S.
      • Lee A.
      • Crowther M.
      • Rodger M.
      • Ginsberg J.S.
      A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy.
      ]. Notably, there was a low DVT prevalence in the study population [
      • Chan W.S.
      • Lee A.
      • Spencer F.A.
      • Crowther M.
      • Rodger M.
      • Ramsay T.
      • et al.
      Predicting deep venous thrombosis in pregnancy: out in "LEFt" field?.
      ]. Another ongoing prospective clinical study aims to evaluate the combined use of the LEFt rule along with D-Dimer testing to accurately exclude DVT in pregnant women (NCT02507180).
      Fig. 1 depicts the diagnostic flowchart for VTE in pregnancy. Initial assessment of suspected DVT in symptomatic pregnant women involves CUS with color flow doppler [
      • Scarsbrook A.F.
      • Evans A.L.
      • Owen A.R.
      • Gleeson F.V.
      Diagnosis of suspected venous thromboembolic disease in pregnancy.
      ]. Ultrasound imaging is preferable because it is risk-free for both mother and fetus, low cost, and readily available at the point-of-care. CUS diagnostic accuracy is high in cases of symptomatic femoropopliteal DVT in the general population (sensitivity: 97%, specificity: 94%). However, in pelvic vein thrombosis (most common in pregnant women), CUS is hindered by the anatomical location of iliofemoral veins and the size of the gravid uterus. CUS combined with the Valsalva maneuver, and with evaluation of venous flow changes with respiration increases the sensitivity for the diagnosis of iliac vein DVT in pregnancy [
      • Palmgren J.
      • Kirkinen P.
      Venous circulation in the maternal lower limb: a doppler study with the valsalva maneuver.
      ]. Recent guidelines on the management of venous thromboembolism in pregnant women from the American Society of Hematology suggest that lower limb CUS for investigation of suspected DVT should include the iliac veins and should be followed by serial imaging if the initial examination is negative or equivocal [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ]. In pregnant women with suspected iliac vein thrombosis, the diagnostic process should be supplemented by magnetic resonance venography if the initial CUS is negative. In cases where compression ultrasound is negative, but clinical suspicion of DVT is high, the diagnostic workup should continue with reassessment on days 3 and 7 with high-sensitive D-dimer testing (if available) and/or repeat CUS. CT venography could be considered in cases of suspected pelvic DVT. The above diagnostic tool with a mean estimated fetal absorbed dose of 25 mGy (under the threshold for fetal risk) should be avoided as it bears the risks of congenital anomalies and growth and mental retardation to the developing fetus [
      • Rademaker J.
      • Griesshaber V.
      • Hidajat N.
      • Oestmann J.W.
      • Felix R.
      Combined CT pulmonary angiography and venography for diagnosis of pulmonary embolism and deep vein thrombosis: radiation dose.
      ]. Instead, magnetic resonance venography is a reliable alternative with high diagnostic accuracy in cases of pelvic thrombosis, without any radiation exposure to mother and fetus [
      • Torkzad M.R.
      • Bremme K.
      • Hellgren M.
      • Eriksson M.J.
      • Hagman A.
      • Jorgensen T.
      • et al.
      Magnetic resonance imaging and ultrasonography in diagnosis of pelvic vein thrombosis during pregnancy.
      ]. Protocols without gadolinium can be considered, as fetal gadolinium exposure (in supraclinical doses) has been associated with developmental abnormalities in small animal models, while evidence in humans is lacking [
      • Cohen S.L.
      • Feizullayeva C.
      • McCandlish J.A.
      • Sanelli P.C.
      • McGinn T.
      • Brenner B.
      • et al.
      Comparison of international societal guidelines for the diagnosis of suspected pulmonary embolism during pregnancy.
      ]. The use of magnetic resonance venography for DVT diagnosis is uncommon in daily practice due to its limited availability at the point-of-care [
      • Patel H.
      • Sun H.
      • Hussain A.N.
      • Vakde T.
      Advances in the diagnosis of venous thromboembolism: a literature review.
      ].
      Fig. 1
      Fig. 1Diagnostic flowchart of VTE in pregnancy
      [
      • van der Pol L.M.
      • Tromeur C.
      • Bistervels I.M.
      • Ni Ainle F.
      • van Bemmel T.
      • Bertoletti L.
      • et al.
      Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism.
      ]
      .

      5. Diagnosis of PE in pregnancy

      The most common non-specific symptoms of PE (i.e. shortness of breath, tachycardia and chest pain), overlap with physiologic changes during pregnancy. Therefore, laboratory workup, diagnostic imaging, patient history, and physical examination are necessary for the accurate and timely diagnosis of PE in pregnancy. The pulmonary embolism rule-out criteria (PERC rule), which are used in the general population to rule-out PE in patients with low pre-test probability for PE, is inadequate in pregnant women [
      • Kline J.A.
      • Slattery D.
      • O'Neil B.J.
      • Thompson J.R.
      • Miller C.D.
      • Schreiber D.
      • et al.
      Clinical features of patients with pulmonary embolism and a negative PERC rule result.
      ]. In a prospective study, the pregnancy-adapted YEARS algorithm was assessed to safely rule out PE without the need for computed tomography angiography (CTA). The YEARS algorithm includes three criteria: (i) clinical signs of DVT, (ii) presence of hemoptysis, and (iii) PE as the most likely diagnosis. PE was safely ruled out and anticoagulation therapy was deferred without CTA imaging if none of the three criteria were met, and D-dimer levels were <1000 ng/ml, or if one or more of the three criteria were met and D-dimer <500 ng/ml [
      • van der Pol L.M.
      • Tromeur C.
      • Bistervels I.M.
      • Ni Ainle F.
      • van Bemmel T.
      • Bertoletti L.
      • et al.
      Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism.
      ]. The use of the YEARS algorithm to reliably exclude PE in pregnant patients was further supported by the findings of another group that retrospectively assessed 371 pregnant women, 77 of which met the criteria for PE exclusion according to the YEARS algorithm, and none of these patients was diagnosed with PE during the initial work-up or 3-month follow-up [
      • Langlois E.
      • Cusson-Dufour C.
      • Moumneh T.A.-O.
      • Elias A.
      • Meyer G.
      • Lacut K.
      ]. Similarly, Righini et al. used the Geneva score with D-dimer to rule-out PE without imaging, thus avoiding the possible side effects of radiation and/or intravenous contrast exposure [
      • Righini M.
      • Robert-Ebadi H.
      • Elias A.
      • Sanchez O.
      • Le Moigne E.
      • Schmidt J.
      • et al.
      Diagnosis of pulmonary embolism during pregnancy.
      ]. However, a recent retrospective secondary analysis of the Diagnosis of Pulmonary Embolism in Pregnancy (DiPEP) study concluded that the accuracy of YEARS algorithm or Geneva score with D-dimer testing to rule-out PE was lower than expected [
      • Goodacre S.
      • Nelson-Piercy C.
      • Hunt B.J.
      • Fuller G.
      Accuracy of PE rule-out strategies in pregnancy: secondary analysis of the DiPEP study prospective cohort.
      ]. The YEARS and Geneva D-dimer methods that rule out PE without imaging would have not recognized 5 out 12 and 3 out of 12 women diagnosed with PE by the DiPEP secondary analysis, where an imaging study was used as a diagnostic gold standard. Van der Pol's group contested the findings of this study due to (i) lack of strict adherence to the YEARS criteria (ii) altered D-dimer levels due to administration of anticoagulation, (iii) lack of definitive diagnosis of PE confirmed by imaging [
      • Mehdipoor G.
      • Bikdeli B.
      • Prince M.R.
      ]. The clinical importance of these differences is not clear and should be addressed in future trials. Therefore, these nuances should be considered when clinicians utilize the YEARS and Geneva/D- dimer methods to rule out PE in pregnancy [
      • van der Pol L.M.
      • Tromeur C.
      • Bistervels I.M.
      • Ni Ainle F.
      • van Bemmel T.
      • Bertoletti L.
      • et al.
      Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism.
      ].
      Another recent development was a new version of the Geneva score (Pregnancy-Adapted Geneva Score or PAG Score) [
      • Robert-Ebadi H.
      • Elias A.
      • Sanchez O.
      • Le Moigne E.
      • Schmidt J.
      • Le Gall C.
      • et al.
      Assessing the clinical probability of pulmonary embolism during pregnancy: the pregnancy-adapted Geneva (PAG) score.
      ]. The authors reported high discriminative power to identify patients with a low, intermediate, or high score, associated with the increasing prevalence of PE, 2.3%, 11.6%, and 61.5%, respectively while the ROC curve was 0.795 for the PAG Score compared to 0.684 for the Geneva score [
      • Robert-Ebadi H.
      • Elias A.
      • Sanchez O.
      • Le Moigne E.
      • Schmidt J.
      • Le Gall C.
      • et al.
      Assessing the clinical probability of pulmonary embolism during pregnancy: the pregnancy-adapted Geneva (PAG) score.
      ].
      The optimal imaging strategy should balance the following factors: (i) missed or delayed diagnosis of PE is associated with significant morbidity and mortality for mother and fetus, (ii) erroneous use of systemic anticoagulants in case of a false-positive diagnosis exposes the mother and fetus to a significant risk of bleeding. Fig. 1 summarizes the diagnostic flowchart for PE in pregnancy. Since PE originates primarily from underlying DVT, CUS is the first investigation of choice in symptomatic patients. In case of negative CUS, chest x-ray follows in routine clinical practice, although its sensitivity to detect PE is limited [
      • Patel H.
      • Sun H.
      • Hussain A.N.
      • Vakde T.
      Advances in the diagnosis of venous thromboembolism: a literature review.
      ]. However, chest X-ray can still be useful in the workup of those patients and can help differentiate from other entities such as pleural effusion, atelectasis or parenchymal opacities [
      • van der Pol L.M.
      • Tromeur C.
      • Faber L.M.
      • van der Hulle T.
      • Kroft L.J.M.
      • Mairuhu A.T.A.
      • et al.
      Chest X-ray not routinely indicated prior to the YEARS algorithm in the diagnostic management of suspected pulmonary embolism.
      ]. RCOG guidelines support chest x-ray as the initial test in obstetric patients presenting with symptoms suggestive of PE [
      • Gynaecologists RCoOa
      Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management.
      ]. However, this practice is contested by recent studies [
      • van der Pol L.M.
      • Tromeur C.
      • Faber L.M.
      • van der Hulle T.
      • Kroft L.J.M.
      • Mairuhu A.T.A.
      • et al.
      Chest X-ray not routinely indicated prior to the YEARS algorithm in the diagnostic management of suspected pulmonary embolism.
      ]. Computational tomography pulmonary angiography (CTPA) or V/Q scan, which are widely used to diagnose PE in the non-pregnant population, are debatable as the first choice of test in pregnant women. Regarding exposure of mother and fetus to radiation, studies have considered CTPA and V/Q scan safe for the diagnosis of PE in pregnancy and puerperium [
      • Tromeur C.
      • van der Pol L.M.
      • Le Roux P.Y.
      • Ende-Verhaar Y.
      • Salaun P.Y.
      • Leroyer C.
      • et al.
      Computed tomography pulmonary angiography versus ventilation-perfusion lung scanning for diagnosing pulmonary embolism during pregnancy: a systematic review and meta-analysis.
      ]. CTPA is more expensive and associated with higher radiation exposure to the mother (especially to the proliferating breast tissue) than to the fetus. V/Q scan is a diagnostic alternative with low radiation exposure (2.5 mSv compared to 8–20 mSv in CTPA) and high sensitivity (97% compared to the CTPA 86%). Additionally, the V/Q scan is free of contrast-related side effects [
      • Strashun A.M.
      A reduced role of V/Q scintigraphy in the diagnosis of acute pulmonary embolism.
      ]. Neither of the two modalities has been associated with a significant increase in the risk of breast cancer [
      • Burton K.R.
      • Park A.L.
      • Fralick M.
      • Ray J.G.
      Risk of early-onset breast cancer among women exposed to thoracic computed tomography in pregnancy or early postpartum.
      ]. CTPA is the preferred imaging modality for PE diagnosis in pregnancy, especially in the US [
      • Roach P.J.
      • Schembri G.P.
      • Bailey D.L.
      V/Q scanning using SPECT and SPECT/CT.
      ]. The American Thoracic Society has suggested the GRADE system (Grades of Recommendation, Assessment, Development, and Evaluation), which recommends any pregnant patient with suspected PE and signs of lower limb DVT undergo CUS. If signs of DVT are absent in CUS, chest X-ray should follow. Patients with a normal or equivocal chest x-ray, but with suspected PE should be considered for a V/Q scan. CTPA is reserved as the last imaging work-up for pregnant patients with equivocal or normal V/Q scans [
      • Leung A.N.
      • Bull T.M.
      • Jaeschke R.
      • Lockwood C.J.
      • Boiselle P.M.
      • Hurwitz L.M.
      • et al.
      American Thoracic Society documents: an official American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline-Evaluation of suspected pulmonary embolism in pregnancy.
      ]. Magnetic resonance pulmonary angiography (MRPA) has potential advantages over CTPA for the diagnosis of PE. Contrast-enhanced MRPA is free of ionizing radiation and provides accurate structural and flow mechanics information [
      • D'Armini A.M.
      Diagnostic advances and opportunities in chronic thromboembolic pulmonary hypertension.
      ]. Gadolinium's potential effects in pregnancy have been discussed in the section “Diagnosis of DVT in pregnancy”. MRI using motion resistant techniques (i.e. steady-state free precession), which do not require contrast administration are being studied for pregnant women. One study found that this contrast-free MRPA technique had comparable results to gadolinium-enhanced scans regarding adequate visualization of all the central and lobar pulmonary arteries, and 90% of the segmental pulmonary arteries [
      • Heredia V.
      • Altun E.
      • Ramalho M.
      • de Campos R.
      • Azevedo R.
      • Pamuklar E.
      • et al.
      MRI of pregnant patients for suspected pulmonary embolism: steady-state free precession vs postgadolinium 3D-GRE.
      ].
      In conclusion, since the diagnosis of VTE in the pregnant population is highly challenging, validated clinical algorithms should guide clinical judgment for optimal detection of the disease.

      6. VTE prophylaxis in pregnancy

      The core principles of VTE prevention in pregnant and postpartum women are similar, despite the differences in recommendation and strategies suggested by different organizations. Every clinical decision should be based on a detailed, documented risk assessment of the VTE risk of each pregnant woman in early pregnancy, upon modification of any of the risk factors and postpartum. Several VTE risk scores have been devised to guide clinical decision-making [
      • O'Shaughnessy F.
      • O'Reilly D.
      • Ni Ainle F.
      Current opinion and emerging trends on the treatment, diagnosis, and prevention of pregnancy-associated venous thromboembolic disease: a review.
      ], some of which have demonstrated clinical significance in guiding appropriate thromboprophylaxis [
      • Chau C.
      • Campagna J.
      • Vial M.
      • Rambeaud C.
      • Loundou A.
      • Bretelle F.
      Use of a personalized iterative score to evaluate risk of venous thromboembolism during pregnancy and puerperium.
      ,
      • Chauleur C.
      • Gris J.C.
      • Laporte S.
      • Chapelle C.
      • Bertoletti L.
      • Equy V.
      • et al.
      Benefit of risk score-guided prophylaxis in pregnant women at risk of thrombotic events: a controlled before-and-after implementation study.
      ], and reducing the incidence of VTE [
      • Chauleur C.
      • Gris J.C.
      • Laporte S.
      • Chapelle C.
      • Bertoletti L.
      • Equy V.
      • et al.
      Benefit of risk score-guided prophylaxis in pregnant women at risk of thrombotic events: a controlled before-and-after implementation study.
      ]. Nevertheless, all of these reports contain limitations in methodology and should be critically assessed by the practicing physician. Even though individual studies have demonstrated that effective thromboprophylaxis prevents VTE in the obstetric population [
      • Lindqvist P.G.
      • Bremme K.
      • Hellgren M.
      Working group on hemostatic disorders SSoO, gynecology. Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism.
      ,
      • Blondon M.
      Thromboprophylaxis after cesarean section: decision analysis.
      ], a systematic review reported a lack of evidence to support these recommendations [
      • Bain E.
      • Wilson A.
      • Tooher R.
      • Gates S.
      • Davis L.J.
      • Middleton P.
      Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period.
      ].

      6.1 Low molecular weight heparin

      By consensus, the recommended agent of pharmacological VTE prophylaxis in pregnant patients is LMWH. LMWH is delivered subcutaneously and safely administered to pregnant and breastfeeding populations [
      • Greer I.A.
      • Nelson-Piercy C.
      Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.
      ]. Clinical recommendations suggest the utilization of low prophylactic or half-therapeutic dose schemes for VTE prophylaxis in pregnant and postpartum women [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ,
      • Bates S.M.
      • Greer I.A.
      • Middeldorp S.
      • Veenstra D.L.
      • Prabulos A.M.
      • Vandvik P.O.
      VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ]. An ongoing clinical trial (NCT 01828697), has been set to answer the question of optimal dosing, comparing a fixed dose of LMWH versus a weight-adjusted dose in terms of VTE prevention. Table 1 summarizes dosing recommendations for anticoagulant prophylaxis and treatment of VTE in pregnancy.
      Table 1Heparin prophylaxis and therapeutic dosing for VTE in the obstetric population
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      .
      FDA pregnancy categoryHalf-lifeMolecular weight (Da)ProphylaxisTreatment
      Unfractionated heparinC0.5-2 h15,0003 × 5000 Units/day

      2 × 7500 Units/day
      Iv; PPT 60–80 s
      Low molecular weight heparinCertoparinB4.6 h56001 × 3000 Units/day2 × 8000 Units/day
      DalteparinB2–2.3 h50001 × 5000 Units/day1 × 200 Units/kg/day

      2 × 100 Units/kg/day
      EnoxaparinB4.5 h45001 × 40 mg/day2 × 1 mg/kg/day
      NadroparinC3.7 h43001 × 2850 Units/day2 × 90 Units/kg/day
      TinzaparinB3.3–3.5 h65001 × 3500 Units/day1 × 175 Units/kg/day
      FondaparinuxB17-21 h17281 × 2.5 mg/day1 × 5 mg/day (<50 kg)

      1 × 7.5 mg/day (50–100 kg)

      1 × 10 mg/day (>100 kg)
      DanaparoidB25 h60002 × 750 Units/dayIv; anti-Xa level 0.5–0.80 IU/ml

      6.2 DOACs

      Evidence of direct oral anticoagulant agents (DOACs) safety for use in VTE prevention in pregnant women is lacking. Nevertheless, the American College of Obstetricians and Gynecologists suggests that DOACs could be considered for thromboprophylaxis in postpartum non-breastfeeding women [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ].

      6.3 Anti-platelets

      The use of aspirin in pregnancy has been extensively studied in the context of antiphospholipid syndrome (APS) and recurrent pregnancy loss (RPL). Several clinical trials and meta-analyses have demonstrated that the combination of LMWH with aspirin improves birth outcomes but has no effect on maternal VTE incidence and severity, in patients with a history of APS/RPL [
      • Fouda U.M.
      • Sayed A.M.
      • Abdou A.M.
      • Ramadan D.I.
      • Fouda I.M.
      • Zaki M.M.
      Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome.
      ,
      • Rai R.
      • Cohen H.
      • Dave M.
      • Regan L.
      Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).
      ,
      • Goel N.
      • Tuli A.
      • Choudhry R.
      The role of aspirin versus aspirin and heparin in cases of recurrent abortions with raised anticardiolipin antibodies.
      ,
      • Kutteh W.H.
      Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.
      ,
      • Mak A.
      • Cheung M.W.
      • Cheak A.A.
      • Ho R.C.
      Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression.
      ,
      • Di Prima F.A.
      • Valenti O.
      • Hyseni E.
      • Giorgio E.
      • Faraci M.
      • Renda E.
      • et al.
      Antiphospholipid syndrome during pregnancy: the state of the art.
      ,
      • Noble L.S.
      • Kutteh W.H.
      • Lashey N.
      • Franklin R.D.
      • Herrada J.
      Antiphospholipid antibodies associated with recurrent pregnancy loss: prospective, multicenter, controlled pilot study comparing treatment with low-molecular-weight heparin versus unfractionated heparin.
      ]. It is recommended that these women with APS/RPL are treated with both low-dose aspirin prophylactic-dose and LWMH. The prophylactic role of aspirin in the pregnant population without APS is being investigated in the PARTUM randomized controlled trial (Postpartum Aspirin to Reduce Thromboembolism Undue Morbidity, NCT04153760) which evaluates low-dose aspirin in the prevention of postpartum VTE. While strong evidence is available for thromboprophylaxis in high-risk pregnant women, optimal prevention of VTE in women with other recognized risk factors is not well supported [
      • Bain E.
      • Wilson A.
      • Tooher R.
      • Gates S.
      • Davis L.J.
      • Middleton P.
      Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period.
      ,
      • McLintock C.
      • Brighton T.
      • Chunilal S.
      • Dekker G.
      • McDonnell N.
      • McRae S.
      • et al.
      Recommendations for the prevention of pregnancy-associated venous thromboembolism.
      ]. Evidence to support mechanical thromboprophylaxis (compression devices e.g. thromboembolic deterrent stockings, pneumatic compression devices) in the obstetric patient is limited [
      • Clark S.L.
      • Christmas J.T.
      • Frye D.R.
      • Meyers J.A.
      • Perlin J.B.
      Maternal mortality in the United States: predictability and the impact of protocols on fatal postcesarean pulmonary embolism and hypertension-related intracranial hemorrhage.
      ]. As a result, mechanical thromboprophylaxis is usually reserved for cases where pharmacological thromboprophylaxis is contraindicated [
      • Gynaecologists RCoOa
      Reducing the Risk of Venous Thromboembolism During Pregnancy and the Puerperium.
      ]. The heterogeneity of evidence has generated substantial variation in VTE prophylaxis guidelines [
      • O'Shaughnessy F.
      • Donnelly J.C.
      • Bennett K.
      • Damkier P.
      • Ainle F.N.
      • Cleary B.J.
      Prevalence of postpartum venous thromboembolism risk factors in an irish urban obstetric population.
      ,
      • Okoroh E.M.
      • Azonobi I.C.
      • Grosse S.D.
      • Grant A.M.
      • Atrash H.K.
      • James A.H.
      Prevention of venous thromboembolism in pregnancy: a review of guidelines, 2000–2011.
      ]. In the United Kingdom, many VTE risk factors are considered for the decision of pharmacological thromboprophylaxis of obstetric patients [
      • Gynaecologists RCoOa
      Reducing the Risk of Venous Thromboembolism During Pregnancy and the Puerperium.
      ]. On the contrary, in North America, pharmacological thromboprophylaxis is uniformly recommended only for patients at the highest risk of VTE [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ,
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Bates S.M.
      • Greer I.A.
      • Middeldorp S.
      • Veenstra D.L.
      • Prabulos A.M.
      • Vandvik P.O.
      VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ]. This heterogeneity of approaches underpins the need for prospective, carefully designed clinical trials to evaluate and establish optimal strategies for the effective prevention of VTE. Considering the scarcity of evidence-based directives, personalized decision-making that incorporates the patient's preference should be followed.

      7. VTE management in pregnancy and postpartum period

      Systemic anticoagulant therapy is the preferred treatment option for most cases of VTE and should be started upon diagnosis. Treatment of VTE in pregnancy requires at least 3 months of anticoagulant therapy (optimally 6 months including the puerperium period) [
      • Beyer-Westendorf J.
      • Michalski F.
      • Tittl L.
      • Middeldorp S.
      • Cohen H.
      • Abdul Kadir R.
      • et al.
      Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting.
      ]. LMWH and unfractionated heparin reduce mortality and recurrence of VTE and are the suggested treatment options in pregnancy [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ]. However, LMWH is more convenient to use in the outpatient setting. Table 1 summarizes dosing recommendations for VTE treatment in pregnancy.

      8. Low molecular weight heparin (LMWH)

      LMWH does not cross the placenta and has not been linked with fetal hemorrhage or teratogen effects on the developing fetus [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ]. It is the treatment of choice in pregnant women due to its tolerability and convenient dosing profile that does not require routine monitoring [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ]. Compared to UFH, LMWH is superior in reducing thrombotic complications, major bleeding, and death. It has similar efficacy in reducing VTE recurrence and equal risk for all-cause bleeding and a lower risk of heparin-induced thrombocytopenia (HIT) [
      • Quinlan D.J.
      • McQuillan A.
      • Eikelboom J.W.
      Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials.
      ,
      • Gould M.K.
      • Dembitzer A.D.
      • Doyle R.L.
      • Hastie T.J.
      • Garber A.M.
      Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.
      ]. Therefore, it is the preferred anticoagulant for pregnant patients with GFR > 30 ml/min [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Lim W.
      • Dentali F.
      • Eikelboom J.W.
      • Crowther M.A.
      Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency.
      ,
      • Rodie V.A.
      • Thomson A.J.
      • Stewart F.M.
      • Quinn A.J.
      • Walker I.D.
      • Greer I.A.
      Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: a case series.
      ]. Of note, most data for the use of LMWH in pregnancy is derived from studies in non-pregnant patients despite the altered pharmacokinetics of the drug in pregnant women. Overall, anti-Xa monitoring has not improved treatment outcomes [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ]. However, it should be considered in specific occasions such as recurrent VTE under anticoagulation therapy, treatment of obese patients, or patients with renal insufficiency [
      • Pabinger I.
      • Greinacher A.
      Anti-factor xa plasma levels in pregnant women receiving low molecular weight heparin thromboprophylaxis.
      ,
      • Boban A.
      • Paulus S.
      • Lambert C.
      • Hermans C.
      The value and impact of anti-xa activity monitoring for prophylactic dose adjustment of low-molecular-weight heparin during pregnancy: a retrospective study.
      ]. In these cases, peak anti-Xa levels are determined 4–6 h after dose administration and the dose is titrated to achieve a level of 0.6 to 1.2 U/ml. Therapeutic levels of anti-Xa are monitored every 4–6 weeks after dose modification [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ].
      LMWH is well tolerated by pregnant women. The most common adverse effect is local bruising and skin irritation at the injection site. If the skin reaction is severe, or causes discomfort, substitution with another LMWH or a non-heparin anticoagulant (fondaparinux, danaparoid) can be considered [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ]. HIT is an uncommon complication in pregnant women under treatment with LMWH (frequency < 0.1%). According to guidelines, monitoring of platelet count is not required in pregnant patients without additional risk factors for HIT [
      • Sagaram D.
      • Siddiq Z.
      • Eisenberger A.B.
      • Ananth C.V.
      • Wright J.D.
      • D'Alton M.E.
      • et al.
      Heparin-induced thrombocytopenia during obstetric hospital admissions.
      ]. In HIT cases, the preferred anticoagulant is danaparoid (transplacental passage has not been documented) [
      • Bates S.M.
      • Greer I.A.
      • Middeldorp S.
      • Veenstra D.L.
      • Prabulos A.M.
      • Vandvik P.O.
      VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ]. Although fondaparinux lacks conclusive evidence regarding transplacental passage and potential risks to the developing fetus, some studies have suggested that it crosses the placenta in small amounts, therefore, it should be avoided during the first trimester [
      • De Carolis S.
      • di Pasquo E.
      • Rossi E.
      • Del Sordo G.
      • Buonomo A.
      • Schiavino D.
      • et al.
      Fondaparinux in pregnancy: could it be a safe option? A review of the literature.
      ].

      9. UFH

      UFH has been used in the past for thromboprophylaxis and the treatment of VTE. UFH is preferred in pregnant patients with renal impairment (GFR < 30 ml/min). UFH can also be considered transitional therapy prior to delivery or surgery because it offers better management of heparin's half-life and rapid reversal of anticoagulation effects. It can be administered intravenously or subcutaneously and dosing needs weight-adjustment [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ].

      10. Oral anticoagulants

      Vitamin K antagonists (warfarin, acenocoumarol) cross the placenta and have been associated with fetal abnormalities, especially between the 6th and 12th week of pregnancy, when the fetus is most vulnerable to vitamin-K deficiency [
      • Vitale N.
      • De Feo M.
      • De Santo L.S.
      • Pollice A.
      • Tedesco N.
      • Cotrufo M.
      Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves.
      ]. Vitamin K antagonists reduce the synthesis of vitamin K-dependent proteins that are essential for normal fetal development and increase the risk for fetal malformations such as bone, central nervous system and ocular abnormalities [
      • D'Souza R.
      • Ostro J.
      • Shah P.S.
      • Silversides C.K.
      • Malinowski A.
      • Murphy K.E.
      • et al.
      Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis.
      ]. Furthermore, their use in the first trimester is associated with an increased potential for fetal loss and an increased risk for fetal cerebral hemorrhage during delivery [
      • Cotrufo M.
      • De Feo M.
      • De Santo L.S.
      • Romano G.
      • Della Corte A.
      • Renzulli A.
      • et al.
      Risk of warfarin during pregnancy with mechanical valve prostheses.
      ,
      • Xu Z.
      • Fan J.
      • Luo X.
      • Zhang W.B.
      • Ma J.
      • Lin Y.B.
      Anticoagulation regimens during pregnancy in patients with mechanical heart valves: a systematic review and meta-analysis.
      ].
      Direct oral anticoagulants (DOAC) (Dabigatran, Rivaroxaban, Apixaban, Edoxaban) have largely substituted the use of Vitamin K antagonists in the treatment and prevention of VTE [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ]. Their safety profile in pregnancy has not been studied thoroughly in humans [
      • van Es N.
      • Coppens M.
      • Schulman S.
      • Middeldorp S.
      • Buller H.R.
      Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials.
      ,
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • Hoffman E.B.
      • Deenadayalu N.
      • Ezekowitz M.D.
      • et al.
      Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials.
      ]. Animal studies have documented their cross-placenta transfer and their presence in breastmilk [
      • Lameijer H.
      • Aalberts J.J.J.
      • van Veldhuisen D.J.
      • Meijer K.
      • Pieper P.G.
      Efficacy and safety of direct oral anticoagulants during pregnancy; a systematic literature review.
      ,
      • Wiesen M.H.
      • Blaich C.
      • Muller C.
      • Streichert T.
      • Pfister R.
      • Michels G.
      The direct factor Xa inhibitor rivaroxaban passes into human breast milk.
      ]. In a study of 223 pregnant women, DOAC exposure was associated with congenital abnormalities in 7/137 neonates [
      • Beyer-Westendorf J.
      • Michalski F.
      • Tittl L.
      • Middeldorp S.
      • Cohen H.
      • Abdul Kadir R.
      • et al.
      Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting.
      ]. Therefore, the use of DOAC in pregnant women and in women trying to conceive is currently contraindicated [
      • Desborough M.J.
      • Pavord S.
      • Hunt B.J.
      Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: comment.
      ].

      11. Treatment considerations pre- and post-delivery

      LMWH should be ceased 24 h prior to scheduled delivery. Alternative treatment regimens that ensure a shorter half-life of heparin or transition to UFH could be considered. Transition to UFH can be considered up to 36 h before delivery and stopped 4–6 h before delivery to facilitate normalization of anti-Xa level [
      • Gynecologists' Committee on Practice B-O
      American College of O
      ACOG practice bulletin no. 196: thromboembolism in pregnancy.
      ,
      • Leffert L.R.
      • Dubois H.M.
      • Butwick A.J.
      • Carvalho B.
      • Houle T.T.
      • Landau R.
      Neuraxial anesthesia in obstetric patients receiving thromboprophylaxis with unfractionated or low-molecular-weight heparin: a systematic review of spinal epidural hematoma.
      ,
      • Bates S.M.
      • Middeldorp S.
      • Rodger M.
      • James A.H.
      • Greer I.
      Guidance for the treatment and prevention of obstetric-associated venous thromboembolism.
      ]. After delivery, anticoagulation can be reinstated 6–12 h after vaginal delivery, 12–24 h after uncomplicated cesarean section or 24 h after epidural catheter removal [
      • Chan W.S.
      • Rey E.
      • Kent N.E.
      • Chan W.S.
      • Kent N.E.
      Group VTEiPGW
      Venous thromboembolism and antithrombotic therapy in pregnancy.
      ]. Notably, the highest VTE risk is observed at 2 weeks postpartum. Therefore, anticoagulant therapy should be continued for a minimum of 6 weeks postpartum to permit for a total treatment duration of at least 3 months [
      • Kamel H.
      • Navi B.B.
      • Sriram N.
      • Hovsepian D.A.
      • Devereux R.B.
      • Elkind M.S.
      Risk of a thrombotic event after the 6-week postpartum period.
      ,
      • McLintock C.
      • Brighton T.
      • Chunilal S.
      • Dekker G.
      • McDonnell N.
      • McRae S.
      • et al.
      Recommendations for the diagnosis and treatment of deep venous thrombosis and pulmonary embolism in pregnancy and the postpartum period.
      ,
      • Kearon C.
      • Akl E.A.
      • Comerota A.J.
      • Prandoni P.
      • Bounameaux H.
      • Goldhaber S.Z.
      • et al.
      Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: american College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ]. Several randomized trials that compared 3-month to >6-month duration of therapy identified that the latter did not lower risk of VTE recurrence, while patients experienced a 2.5-fold increase in major bleeding events [
      • Kearon C.
      • Akl E.A.
      • Comerota A.J.
      • Prandoni P.
      • Bounameaux H.
      • Goldhaber S.Z.
      • et al.
      Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: american College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ]. Moreover, a meta-analysis of individual patient data from randomized trials that attempted to compare, treatment of 3 months compared with >6 months revealed that although anticoagulants are effective at preventing VTE recurrence while patients are on therapy, the risk of recurrence is comparable after cessation of therapy [
      • Boutitie F.
      • Pinede L.
      • Schulman S.
      • Agnelli G.
      • Raskob G.
      • Julian J.
      • et al.
      Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials.
      ].
      LMWH or UFH are acceptable options for continued treatment postpartum. Alternative options include fondaparinux or warfarin. Evidence on the effects of these anticoagulants in neonatal bleeding is limited. Nevertheless, their use is considered safe for the newborn based on the results of observational studies [
      • Richter C.
      • Sitzmann J.
      • Lang P.
      • Weitzel H.
      • Huch A.
      • Huch R.
      Excretion of low molecular weight heparin in human milk.
      ]. DOAC safety profile has not been studied thoroughly in breastfeeding women, therefore they are not recommended as treatment [
      • Wiesen M.H.
      • Blaich C.
      • Muller C.
      • Streichert T.
      • Pfister R.
      • Michels G.
      The direct factor Xa inhibitor rivaroxaban passes into human breast milk.
      ,
      • Burnett A.E.
      • Mahan C.E.
      • Vazquez S.R.
      • Oertel L.B.
      • Garcia D.A.
      • Ansell J.
      Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment.
      ].

      12. Advanced treatment options

      Anticoagulant therapy is adequate for most cases of VTE in pregnancy. However, in cases of massive PE (acute PE accompanied by systemic hypotension, pulselessness, or persistent bradycardia with signs/symptoms of shock) advanced therapies are required [
      • Jaff M.R.
      • McMurtry M.S.
      • Archer S.L.
      • Cushman M.
      • Goldenberg N.
      • Goldhaber S.Z.
      • et al.
      Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association.
      ]. These therapies include systemic thrombolysis, surgical thrombectomy, catheter-directed thrombectomy/thrombolysis, or extracorporeal membrane oxygenation (ECMO) [
      • Bates S.M.
      • Rajasekhar A.
      • Middeldorp S.
      • McLintock C.
      • Rodger M.A.
      • James A.H.
      • et al.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ]. Catheter-directed thrombolysis or thrombectomy is an option for patients with limb-threatening proximal DVT. Advanced treatment options can also be considered in cases with sub-massive PE (manifesting with right ventricular dysfunction or myocardial necrosis without hypotension) [
      • Jaff M.R.
      • McMurtry M.S.
      • Archer S.L.
      • Cushman M.
      • Goldenberg N.
      • Goldhaber S.Z.
      • et al.
      Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association.
      ].

      13. Thrombolysis

      Systemic thrombolytics such as tenecteplase and alteplase are molecules that promote the conversion of plasminogen to plasmin and facilitate the degradation of fibrin molecules [
      • Bell W.R.
      Present-day thrombolytic therapy: therapeutic agents–pharmacokinetics and pharmacodynamics.
      ]. Thrombolysis can promptly improve patient's hemodynamic status and symptoms and increase survival. Additionally, thrombolysis limits damage to the right ventricle and lowers the possibility of another PE [
      • Bell W.R.
      Present-day thrombolytic therapy: therapeutic agents–pharmacokinetics and pharmacodynamics.
      ]. However, the potential benefits come at the cost of increased bleeding risk (intracranial hemorrhage, major bleeding, or fatal hemorrhage) and possible placenta-related adverse effects (placental abruption, premature labor, fetal demise) [
      • Bell W.R.
      Present-day thrombolytic therapy: therapeutic agents–pharmacokinetics and pharmacodynamics.
      ,
      • Marti C.
      • John G.
      • Konstantinides S.
      • Combescure C.
      • Sanchez O.
      • Lankeit M.
      • et al.
      Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis.
      ,
      • Pfeifer G.W.
      Distribution and placental transfer of 131-I streptokinase.
      ]. Transplacental passage of tissue plasminogen activator and streptokinase is negligible and has not been linked with fetal coagulopathy or other malformations [
      • Pfeifer G.W.
      Distribution and placental transfer of 131-I streptokinase.
      ,
      • te Raa G.D.
      • Ribbert L.S.
      • Snijder R.J.
      • Biesma D.H.
      Treatment options in massive pulmonary embolism during pregnancy; a case-report and review of literature.
      ,
      • Capstick T.
      • Henry M.T.
      Efficacy of thrombolytic agents in the treatment of pulmonary embolism.
      ]. Based on a few cases of thrombolysis used for VTE in pregnancy, a literature review reported 2.8% (4/141) deaths of pregnant women and 1.4% (2/141) neonatal deaths [
      • Sousa Gomes M.
      • Guimaraes M.
      • Montenegro N.
      Thrombolysis in pregnancy: a literature review.
      ]. The mortality rate of thrombolysis used for the treatment of PE in non-pregnant patients was found to be 2.17% (23/1061), in a recent meta-analysis [
      • Sousa Gomes M.
      • Guimaraes M.
      • Montenegro N.
      Thrombolysis in pregnancy: a literature review.
      ,
      • Chatterjee S.
      • Chakraborty A.
      • Weinberg I.
      • Kadakia M.
      • Wilensky R.L.
      • Sardar P.
      • et al.
      Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.
      ]. A meta-analysis of studies on the use of systemic thrombolysis in antepartum and postpartum women reported a 28.4% risk for major bleeding (primarily vaginal hemorrhage or intra-abdominal bleeding depending on the mode of delivery) [
      • Marti C.
      • John G.
      • Konstantinides S.
      • Combescure C.
      • Sanchez O.
      • Lankeit M.
      • et al.
      Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis.
      ,
      • Martillotti G.
      • Boehlen F.
      • Robert-Ebadi H.
      • Jastrow N.
      • Righini M.
      • Blondon M.
      Treatment options for severe pulmonary embolism during pregnancy and the postpartum period: a systematic review.
      ].
      Thrombolytic agents can be administered through a multi-side-hole catheter that is advanced intravascularly to the site of the thrombus. This method is known as catheter-directed thrombolysis and has the theoretical advantages of lower bleeding risk and no transplacental passage of the lytic agents since they are delivered directly into the thrombus [
      • Gartman E.J.
      The use of thrombolytic therapy in pregnancy.
      ,
      • Mastoris I.
      • Kokkinidis D.G.
      • Bikakis I.
      • Archontakis-Barakakis P.
      • Papanastasiou C.A.
      • Jonnalagadda A.K.
      • et al.
      Catheter-directed thrombolysis vs. Anticoagulation for the prevention and treatment of post-thrombotic syndrome in deep vein thrombosis: an updated systematic review and meta-analysis of randomized trials.
      ]. Catheter-directed thrombolysis seems to offer the advantage of lower risk for bleeding compared to systemic thrombolysis, although more data is needed for confirmation [
      • Konstantinides S.V.
      • Meyer G.
      • Becattini C.
      • Bueno H.
      • Geersing G.J.
      • Harjola V.P.
      • et al.
      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).
      ]. This technique can be combined with mechanical methods of clot retrieval such as aspiration thrombectomy (direct aspiration of thrombus from the vein using a catheter, a device or a sheath), balloon maceration (fragmentation of thrombus using an angioplasty balloon), balloon angioplasty (dilation of the venous lumen using inflating a catheter-bound balloon) with or without stent placement (deployment of a metallic endoprosthesis to scaffold the dilated venous lumen) [
      • Kokkinidis D.G.
      • Armstrong E.J.
      Current developments in endovascular therapy of peripheral vascular disease.
      ].

      14. Inferior vena cava (IVC) filters

      IVC filter placement is considered in cases where anticoagulation therapy is contraindicated, ineffective (recurrent VTE on full-dose anticoagulation therapy), or not well tolerated because of complications such as heparin-induced thrombocytopenia, heparin allergy or significant bleeding during anticoagulation therapy [
      • Harris S.A.
      • Velineni R.
      • Davies A.H.
      Inferior vena cava filters in pregnancy: a systematic review.
      ]. Their placement involves exposure of mother and fetus to ionizing radiation, which could adversely impact the early stages of fetal development, therefore, it should be avoided unless the benefits clearly outweigh risks. Proposed techniques to limit radiation exposure to fetus include using a lead abdominal shield and intravascular ultrasound guidance for IVC filter placement. IVC filters have been successfully deployed through the jugular or femoral access without impediment by the gravid uterus in all trimesters of pregnancy. Infrarenal placement has been associated with compression by the gravid uterus and possible displacement that can lead to migration or fracture of the filter or endothelial damage to IVC. On the contrary, suprarenal placement offers the advantages of accelerated venous flow (from the convergence of blood flow from renal veins) which can facilitate the lysis of thrombi and protect from thrombi originating from the ovarian veins. Therefore, it is the preferred method of IVC filter placement [
      • Harris S.A.
      • Velineni R.
      • Davies A.H.
      Inferior vena cava filters in pregnancy: a systematic review.
      ]. Theoretically, retrievable filters are an attractive option for pregnant patients, due to their young age and transient hypercoagulable state. Of note, a randomized control trial in non-pregnant patients treated with IVC filter for proximal DVT, suggested that the long-term presence (8 years) of IVC filters is associated with an increased risk for DVT and has no survival benefit [
      Group PS
      Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du risque d'Embolie pulmonaire par interruption Cave) randomized study.
      ]. In a study of retrievable IVC filters in pregnancy, the overall complication rate was 25% and rate of successful removal was 81%.
      Complications related to IVC filter placement include threatened preterm labor, leg swelling and retroperitoneal hematoma. Other reported complications are DVT (including filter and IVC thrombosis), filter occlusion, tilt, fracture, filter migration and failed retrieval [
      • Harris S.A.
      • Velineni R.
      • Davies A.H.
      Inferior vena cava filters in pregnancy: a systematic review.
      ,
      • Liu Y.
      • Sun Y.
      • Zhang S.
      • Jin X.
      Placement of a retrievable inferior vena cava filter for deep venous thrombosis in term pregnancy.
      ]. To date, no randomized clinical trials have assessed the effectiveness and risks of IVC filter placement in pregnancy, therefore, IVC filters should be considered for the same absolute indications as in non-pregnant population, ideally, by a multidisciplinary team of experts.

      15. Other invasive VTE treatment options and supportive measures

      Surgical thrombectomy, percutaneous catheter thrombectomy, extracorporeal membrane oxygenation (ECMO) are other invasive treatment options available for VTE in pregnancy and puerperium. In a series of 127 pregnant or peripartum women with massive PE, 36 were treated with surgical thrombectomy, 7 were treated with percutaneous catheter thrombectomy and 3 were treated with ECMO and anticoagulation. Patients treated with surgical thrombectomy had a survival rate of 86%, major bleeding rate of 20%, fetal death rate of 20% and premature delivery rate of 8%. Percutaneous catheter thrombectomy was associated with a survival rate of 100%, major bleeding rate of 20% and fetal death rate of 25%. In 2/7 women, this method was insufficient and led to escalation with other treatments (ECMO or surgical thrombectomy). ECMO for 4–10 days was used in 3/127 cases. All patients survived without any major bleeding and there was one documented premature delivery [
      • Martillotti G.
      • Boehlen F.
      • Robert-Ebadi H.
      • Jastrow N.
      • Righini M.
      • Blondon M.
      Treatment options for severe pulmonary embolism during pregnancy and the postpartum period: a systematic review.
      ]. Due to the lack of randomized clinical trials and a small number of patients included in this case series, this data should be used cautiously. Nevertheless, percutaneous and surgical thrombectomy could be viable alternatives to thrombolysis, especially early postpartum, to avoid the risk of massive postpartum hemorrhage related to thrombolytic therapy. These procedures should be conducted in specialized centers with available supportive measures (cardiopulmonary by-pass), by skilled medical professionals.

      16. Conclusion

      The physiologic changes associated with pregnancy and the postpartum period raise the risk of VTE. VTE and its complications are major causes of maternal and fetal morbidity and mortality. Therefore, prompt and effective identification of women who will benefit mostly from preventive anticoagulation is of paramount importance. VTE diagnosis in pregnancy can be optimized following an algorithmic approach where CUS has a central role. MR and CT venography, D-dimers and serial CUS are integral parts of the algorithm. When PE is suspected, an X-ray, CTPA and V/Q scan can help establish the diagnosis. Prevention and treatment decisions in the obstetric population are challenging because of the limited data regarding the safety and efficacy of anticoagulants in such patients and the critical time for the developing fetus. The primary anticoagulation choice in pregnancy is LMWH and should be administered for a minimum of 3 months. Advanced treatments such as thrombolysis, IVC filters and mechanical methods of thrombus removal can be associated with significant fetal morbidity and mortality and should be considered under special circumstances such as failure of other treatments, massive or sub-massive PE, or acute limb-threatening DVT. Overall, decision-making should be supported by guideline recommendations, careful consideration of benefits and risks for the mother and the developing fetus, availability of resources and level of expertise, and the patient's ethical code and preference.

      Declaration of competing interest

      The authors have no conflict of interest to declare. All authors have accepted the contents of manuscript submitted.

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