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Venous thromboembolism during pregnancy and postpartum period

Published:December 20, 2021DOI:https://doi.org/10.1016/j.ejim.2021.12.013

      Highlights

      • VTE is one of the leading etiologies of maternal morbidity and mortality, which is potentially preventable.
      • Rates of VTE during pregnancy and postpartum have not decreased over the past two decades.
      • CTPA is the preferred diagnostic modality for suspected PE, especially with modern low-dose techniques further reducing the radiation exposure.
      • 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.

      Keywords

      1. Introduction

      The maternal mortality rates in the United States (US) remain the highest among developed countries, and continue to rise (
      • MacDorman MF
      • Declercq E
      • Cabral H
      • Morton C.
      Recent Increases in the U.S. Maternal Mortality Rate: Disentangling Trends From Measurement Issues.
      ). Cardiovascular diseases are the leading etiology of maternal deaths in developed countries (
      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.
      ), and account for more than a third of pregnancy-related deaths. Most importantly many are preventable (
      • Petersen EE
      • Davis NL
      • Goodman D
      • Cox S
      • Mayes N
      • Johnston E
      • Syverson C
      • Seed K
      • Shapiro-Mendoza CK
      • Callaghan WM
      • Barfield W.
      Vital Signs: Pregnancy-Related Deaths, United States, 2011-2015, and Strategies for Prevention, 13 States, 2013-2017.
      ). 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 (
      • Petersen EE
      • Davis NL
      • Goodman D
      • Cox S
      • Mayes N
      • Johnston E
      • Syverson C
      • Seed K
      • Shapiro-Mendoza CK
      • Callaghan WM
      • Barfield W.
      Vital Signs: Pregnancy-Related Deaths, United States, 2011-2015, and Strategies for Prevention, 13 States, 2013-2017.
      ), accounting for ∼9% of pregnancy-related deaths (
      • Abe K
      • Kuklina EV
      • Hooper WC
      • Callaghan WM.
      Venous thromboembolism as a cause of severe maternal morbidity and mortality in the United States.
      ). 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 (
      • Wik HS
      • Jacobsen AF
      • Sandvik L
      • Sandset PM.
      Prevalence and predictors for post-thrombotic syndrome 3 to 16 years after pregnancy-related venous thrombosis: a population-based, cross-sectional, case-control study.
      ). VTE is often triggered by specific pregnancy-related conditions, some of which are potentially preventable (
      • Testa S
      • Passamonti SM
      • Paoletti O
      • Bucciarelli P
      • Ronca E
      • Riccardi A
      • Rigolli A
      • Zimmermann A
      • The Martinelli I.
      Pregnancy Health-care Program" for the prevention of venous thromboembolism in pregnancy.
      ). 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) (
      • Parunov LA
      • Soshitova NP
      • Ovanesov MV
      • Panteleev MA
      • Serebriyskiy II.
      Epidemiology of venous thromboembolism (VTE) associated with pregnancy.
      ). 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 (
      • Sultan AA
      • West J
      • Tata LJ
      • Fleming KM
      • Nelson-Piercy C
      • Grainge MJ.
      Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study.
      ,
      • Pomp ER
      • Lenselink AM
      • Rosendaal FR
      • Doggen CJ.
      Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study.
      ).
      A meta-analysis of 20 studies including > 93 million pregnant and postpartum women showed that the incidence of VTE was 1.2 per 1000 deliveries (
      • Kourlaba G
      • Relakis J
      • Kontodimas S
      • Holm MV
      Maniadakis N. A systematic review and meta-analysis of the epidemiology and burden of venous thromboembolism among pregnant women.
      ). 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) (
      • Callaghan WM
      • Creanga AA
      • Kuklina EV.
      Severe maternal morbidity among delivery and postpartum hospitalizations in the United States.
      ). 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 (
      • Wiener RS
      • Schwartz LM
      • Woloshin S.
      Time trends in pulmonary embolism in the United States: evidence of overdiagnosis.
      ). 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) (
      • Elgendy IY
      • Gad MM
      • Mansoor H
      • Mahmoud AN
      • Elbadawi A
      • Saad A
      • Saad M
      • Elkaryoni A
      • Secemsky EA
      • Mamas MA
      • Monreal M
      • Weinberg I
      • Pepine CJ.
      Acute pulmonary embolism during pregnancy and puerperium: National trends and in-hospital outcomes.
      ). 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) (
      • Sultan AA
      • West J
      • Tata LJ
      • Fleming KM
      • Nelson-Piercy C
      • Grainge MJ.
      Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study.
      ).
      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) (
      • James AH
      • Jamison MG
      • Brancazio LR
      • Myers ER.
      Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality.
      ). This could be attributed to the increased prevalence of some of the risk factors including sickle cell disease and hypertension among Black women (
      • Karlsson O
      • Sporrong T
      • Hillarp A
      • Jeppsson A
      • Hellgren M.
      Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy.
      ). 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) (
      • Elgendy IY
      • Gad MM
      • Mansoor H
      • Mahmoud AN
      • Elbadawi A
      • Saad A
      • Saad M
      • Elkaryoni A
      • Secemsky EA
      • Mamas MA
      • Monreal M
      • Weinberg I
      • Pepine CJ.
      Acute pulmonary embolism during pregnancy and puerperium: National trends and in-hospital outcomes.
      ).

      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 (
      • Cerneca F
      • Ricci G
      • Simeone R
      • Malisano M
      • Alberico S
      • Guaschino S.
      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.
      ,
      • Karlsson O
      • Sporrong T
      • Hillarp A
      • Jeppsson A
      • Hellgren M.
      Prospective longitudinal study of thromboelastography and standard hemostatic laboratory tests in healthy women during normal pregnancy.
      ,
      • Maiello M
      • Torella M
      • Caserta L
      • Caserta R
      • Sessa M
      • Tagliaferri A
      • Bernacchi M
      • Napolitano M
      • Nappo C
      • De Lucia D
      • Panariello S.
      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 (
      • Ikard RW
      • Ueland K
      • Folse R.
      Lower limb venous dynamics in pregnant women.
      ). There are also immunological changes, with cytokine surge and vascular endothelial dysfunction that could predispose to VTE (
      • van Pampus MG
      • Dekker GA
      • Wolf H
      • Huijgens PC
      • Koopman MM
      • von Blomberg BM
      • Büller HR
      High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia.
      ) (Fig. 1).
      Fig. 1:
      Fig. 1Pathophysiology of venous thromboembolism in pregnancy.
      Key pathophysiological mechanisms include immunomodulatory changes, hypercoagulability, hemodynamic changes and venous stasis.

      4. Risk factors

      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 (
      • Elgendy IY
      • Fogerty A
      • Blanco-Molina Á
      • Rosa V
      • Schellong S
      • Skride A
      • Portillo J
      • Lopez-Miguel P
      • Monreal M
      • Weinberg I.
      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 (
      • Elgendy IY
      • Fogerty A
      • Blanco-Molina Á
      • Rosa V
      • Schellong S
      • Skride A
      • Portillo J
      • Lopez-Miguel P
      • Monreal M
      • Weinberg I.
      Clinical Characteristics and Outcomes of Women Presenting with Venous Thromboembolism during Pregnancy and Postpartum Period: Findings from the RIETE Registry.
      ).
      Table 1Risk factors for VTE in pregnancy.
      Preexisting risk factors
      Older maternal age
      Prior VTE
      Active cancer
      Thrombophilia
      Immobilization
      Recent prolonged travel
      Recent surgery
      Obesity
      Smoking
      Family history of VTE
      Pregnancy-specific risk factors
      Cesarean delivery
      In vitro fertilization
      Pre-eclampsia
      Infections
      Multiple pregnancies
      Primiparity
      Gestational diabetes
      VTE: venous thromboembolism

      4.1 Pre-existing risk factors

      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 (
      • Elgendy IY
      • Gad MM
      • Mansoor H
      • Mahmoud AN
      • Elbadawi A
      • Saad A
      • Saad M
      • Elkaryoni A
      • Secemsky EA
      • Mamas MA
      • Monreal M
      • Weinberg I
      • Pepine CJ.
      Acute pulmonary embolism during pregnancy and puerperium: National trends and in-hospital outcomes.
      ,
      • James AH
      • Jamison MG
      • Brancazio LR
      • Myers ER.
      Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality.
      ,
      • Elgendy IY
      • Fogerty A
      • Blanco-Molina Á
      • Rosa V
      • Schellong S
      • Skride A
      • Portillo J
      • Lopez-Miguel P
      • Monreal M
      • Weinberg I.
      Clinical Characteristics and Outcomes of Women Presenting with Venous Thromboembolism during Pregnancy and Postpartum Period: Findings from the RIETE Registry.
      ,
      • Jacobsen AF
      • Skjeldestad FE
      • Sandset PM.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium–a register-based case-control study.
      ). The risk of VTE increases with advanced maternal age (
      • Elgendy IY
      • Gad MM
      • Mansoor H
      • Mahmoud AN
      • Elbadawi A
      • Saad A
      • Saad M
      • Elkaryoni A
      • Secemsky EA
      • Mamas MA
      • Monreal M
      • Weinberg I
      • Pepine CJ.
      Acute pulmonary embolism during pregnancy and puerperium: National trends and in-hospital outcomes.
      ). 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) (
      • Larsen TB
      • Sørensen HT
      • Gislum M
      • Johnsen SP.
      Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study.
      ). 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 (
      • Elgendy IY
      • Gad MM
      • Mansoor H
      • Mahmoud AN
      • Elbadawi A
      • Saad A
      • Saad M
      • Elkaryoni A
      • Secemsky EA
      • Mamas MA
      • Monreal M
      • Weinberg I
      • Pepine CJ.
      Acute pulmonary embolism during pregnancy and puerperium: National trends and in-hospital outcomes.
      ).
      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 (
      • Pabinger I
      • Grafenhofer H
      • Kyrle PA
      • Quehenberger P
      • Mannhalter C
      • Lechner K
      • Kaider A.
      Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism.
      ). 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%) (
      • Rodger M.
      Pregnancy and venous thromboembolism: 'TIPPS' for risk stratification.
      ).
      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) (
      • Liu S
      • Rouleau J
      • Joseph KS
      • Sauve R
      • Liston RM
      • Young D
      • Kramer MS.
      Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada.
      ). The absolute risk of PE and DVT separately in women with thrombophilia is as high as 43 and 146 per 10,000 deliveries, respectively (
      • Liu S
      • Rouleau J
      • Joseph KS
      • Sauve R
      • Liston RM
      • Young D
      • Kramer MS.
      Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada.
      ). 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) (
      • Robertson L
      • Wu O
      • Langhorne P
      • Twaddle S
      • Clark P
      • Lowe GD
      • Walker ID
      • Greaves M
      • Brenkel I
      • Regan L
      • Greer IA
      Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review.
      ).

      4.2 Pregnancy-specific risk factors

      4.2.1 Cesarean delivery

      Cesarean delivery is associated with increased risk of VTE compared with vaginal delivery (OR 4.9, 95% CI 3.8–6.3) (
      • Lindqvist P
      • Dahlbäck B
      • Marŝál K.
      Thrombotic risk during pregnancy: a population study.
      ). Cesarean delivery is associated with a higher risk of PE (OR 2.9, 95% CI 2.4–3.5) as compared with DVT (OR 1.8, 95% CI 1.6–2.0) (
      • Liu S
      • Rouleau J
      • Joseph KS
      • Sauve R
      • Liston RM
      • Young D
      • Kramer MS.
      Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada.
      ). Compared with planned surgical delivery, emergency delivery confers a higher risk of VTE (
      • Jacobsen AF
      • Skjeldestad FE
      • Sandset PM.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium–a register-based case-control study.
      ,
      • Kane EV
      • Calderwood C
      • Dobbie R
      • Morris C
      • Roman E
      • Greer IA.
      A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005.
      ). 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) (
      • Jacobsen AF
      • Skjeldestad FE
      • Sandset PM.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium–a register-based case-control study.
      ). 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) (
      • Kane EV
      • Calderwood C
      • Dobbie R
      • Morris C
      • Roman E
      • Greer IA.
      A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005.
      ). Cesarean delivery is associated with activation of the coagulation cascade as well as uteroplacental surface alterations which increase the risk of thrombogenicity (
      • Epiney M
      • Boehlen F
      • Boulvain M
      • Reber G
      • Antonelli E
      • Morales M
      • Irion O
      • De Moerloose P.
      D-dimer levels during delivery and the postpartum.
      ). In addition, physical activity might be reduced following cesarean delivery with delayed recovery in mobility for at few days following delivery (
      • Sharma R
      • Atkin H
      • Mackillop L
      • Paterson-Brown S.
      Assessment of the mobility of mothers postpartum to identify those at greatest risk of venous thromboembolism.
      ,
      • Leth RA
      • Møller JK
      • Thomsen RW
      • Uldbjerg N
      • Nørgaard M.
      Risk of selected postpartum infections after cesarean section compared with vaginal birth: a five-year cohort study of 32,468 women.
      ).

      4.2.2 In vitro fertilization

      In vitro fertilization (IVF) pregnancies are associated with higher risk of VTE compared with normal pregnancies (
      • Hansen AT
      • Kesmodel US
      • Juul S
      • Hvas AM.
      Increased venous thrombosis incidence in pregnancies after in vitro fertilization.
      ,
      • Jacobsen AF
      • Skjeldestad FE
      • Sandset PM.
      Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study.
      ). 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 (
      • Hansen AT
      • Kesmodel US
      • Juul S
      • Hvas AM.
      Increased venous thrombosis incidence in pregnancies after in vitro fertilization.
      ). 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) (
      • Hansen AT
      • Kesmodel US
      • Juul S
      • Hvas AM.
      Increased venous thrombosis incidence in pregnancies after in vitro fertilization.
      ). 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) (
      • Grandone E
      • Di Micco PP
      • Villani M
      • Colaizzo D
      • Fernández-Capitán C
      • Del Toro J
      • Rosa V
      • Bura-Riviere A
      • Quere I
      • Blanco-Molina Á
      • Margaglione M
      • Monreal M
      RIETE Investigators. Venous Thromboembolism in Women Undergoing Assisted Reproductive Technologies: Data from the RIETE Registry.
      ). 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 (
      • Henriksson P
      • Westerlund E
      • Wallén H
      • Brandt L
      • Hovatta O
      • Ekbom A.
      Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study.
      ). 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 (
      • Nelson SM
      • Greer IA
      The potential role of heparin in assisted conception.
      ).

      4.2.3 Pre-eclampsia

      Pre-eclampsia is associated with an increased risk of VTE in the postpartum period (
      • Jacobsen AF
      • Skjeldestad FE
      • Sandset PM.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium–a register-based case-control study.
      ,
      • Lindqvist P
      • Dahlbäck B
      • Marŝál K.
      Thrombotic risk during pregnancy: a population study.
      ,
      • Kane EV
      • Calderwood C
      • Dobbie R
      • Morris C
      • Roman E
      • Greer IA.
      A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005.
      ). 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 (
      • Kane EV
      • Calderwood C
      • Dobbie R
      • Morris C
      • Roman E
      • Greer IA.
      A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005.
      ). However, the risk was not increased during the antepartum period (IRR 1.03; 95% CI 0.76–1.39) (
      • Kane EV
      • Calderwood C
      • Dobbie R
      • Morris C
      • Roman E
      • Greer IA.
      A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005.
      ). 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) (
      • Lindqvist P
      • Dahlbäck B
      • Marŝál K.
      Thrombotic risk during pregnancy: a population study.
      ). 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 (
      • Levine RJ
      • Maynard SE
      • Qian C
      • Lim KH
      • England LJ
      • Yu KF
      • Schisterman EF
      • Thadhani R
      • Sachs BP
      • Epstein FH
      • Sibai BM
      • Sukhatme VP
      • Karumanchi SA.
      Circulating angiogenic factors and the risk of preeclampsia.
      ). The increased expression of procoagulant factors, attenuation of endogenous anticoagulant activity, and increased platelet activity have all been implicated in the prothrombotic tendency (
      • Peraçoli MT
      • Menegon FT
      • Borges VT
      • de Araújo Costa RA
      • Thomazini-Santos IA
      • Peraçoli JC.
      Platelet aggregation and TGF-beta(1) plasma levels in pregnant women with preeclampsia.
      ).

      4.2.4 Infections

      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) (
      • Hauth J.
      MFMU cesarean registry: thromboembolism—occurrence and risk factors in 39,285 cesarean births.
      ). 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) (
      • Cerneca F
      • Ricci G
      • Simeone R
      • Malisano M
      • Alberico S
      • Guaschino S.
      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) (
      • Sultan AA
      • Tata LJ
      • West J
      • Fiaschi L
      • Fleming KM
      • Nelson-Piercy C
      • Grainge MJ.
      Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom.
      ). 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 (
      • Levi M
      • Keller TT
      • van Gorp E
      • ten Cate H.
      Infection and inflammation and the coagulation system.
      ).

      5. Clinical Presentation and Diagnosis

      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 (
      • Kline JA
      • Richardson DM
      • Than MP
      • Penaloza A
      • Roy PM.
      Systematic review and meta-analysis of pregnant patients investigated for suspected pulmonary embolism in the emergency department.
      ,
      • van Es N
      • van der Hulle T
      • van Es J
      • den Exter PL
      • Douma RA
      • Goekoop RJ
      • Mos IC
      • Galipienzo J
      • Kamphuisen PW
      • Huisman MV
      • Klok FA
      • Büller HR
      • Bossuyt PM.
      Wells Rule and d-Dimer Testing to Rule Out Pulmonary Embolism: A Systematic Review and Individual-Patient Data Meta-analysis.
      ). 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 (
      • Wells PS
      • Anderson DR
      • Rodger M
      • Ginsberg JS
      • Kearon C
      • Gent M
      • Turpie AG
      • Bormanis J
      • Weitz J
      • Chamberlain M
      • Bowie D
      • Barnes D
      • Hirsh J.
      Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.
      ,
      • van Belle A
      • Büller HR
      • Huisman MV
      • Huisman PM
      • Kaasjager K
      • Kamphuisen PW
      • Kramer MH
      • Kruip MJ
      • Kwakkel-van Erp JM
      • Leebeek FW
      • Nijkeuter M
      • Prins MH
      • Sohne M
      • Tick LW
      Christopher Study Investigators
      Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography.
      ,
      • Touhami O
      • Marzouk SB
      • Bennasr L
      • Touaibia M
      • Souli I
      • Felfel MA
      • Kehila M
      • Channoufi MB
      • Magherbi HE.
      Are the Wells Score and the Revised Geneva Score valuable for the diagnosis of pulmonary embolism in pregnancy?.
      ). 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 (
      • Murphy N
      • Broadhurst DI
      • Khashan AS
      • Gilligan O
      • Kenny LC
      • O'Donoghue K
      Gestation-specific D-dimer reference ranges: a cross-sectional study.
      ,
      • Ercan Ş
      • Özkan S
      • Yücel N
      • Orçun A.
      Establishing reference intervals for D-dimer to trimesters.
      ). 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 (
      • Righini M
      • Robert-Ebadi H
      • Elias A
      • Sanchez O
      • Le Moigne E
      • Schmidt J
      • Le Gall C
      • Cornuz J
      • Aujesky D
      • Roy PM
      • Chauleur C
      • Rutschmann OT
      • Poletti PA
      • Le Gal G
      CT-PE-Pregnancy Group
      Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study.
      ) (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 (
      • van der Pol LM
      • Tromeur C
      • Bistervels IM
      • Ni Ainle F
      • van Bemmel T
      • Bertoletti L
      • Couturaud F
      • van Dooren YPA
      • Elias A
      • Faber LM
      • Hofstee HMA
      • van der Hulle T
      • Kruip MJHA
      • Maignan M
      • Mairuhu ATA
      • Middeldorp S
      • Nijkeuter M
      • Roy PM
      • Sanchez O
      • Schmidt J
      • Ten Wolde M
      • Klok FA
      • Huisman MV
      Artemis Study Investigators. Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism.
      ).
      Fig. 2:
      Fig. 2Diagnostic workup for a suspected acute venous thromboembolism in pregnancy.
      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.
      VTE: venous thromboembolism; DVT: deep venous thrombosis; PE: pulmonary embolism; DUS: lower extremity duplex ultrasonography; CTPA: computed tomographic pulmonary angiography.
      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) (
      • Konstantinides SV
      • Meyer G
      • Becattini C
      • Bueno H
      • Geersing GJ
      • Harjola VP
      • Huisman MV
      • Humbert M
      • Jennings CS
      • Jiménez D
      • Kucher N
      • Lang IM
      • Lankeit M
      • Lorusso R
      • Mazzolai L
      • Meneveau N
      • Áinle FN
      • Prandoni P
      • Pruszczyk P
      • Righini M
      • Torbicki A
      • Van Belle E
      • Zamorano JL
      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 (
      • Chan WS
      • Spencer FA
      • Ginsberg JS.
      Anatomic distribution of deep vein thrombosis in pregnancy.
      ,
      • MacDorman MF
      • Declercq E
      • Cabral H
      • Morton C.
      Recent Increases in the U.S. Maternal Mortality Rate: Disentangling Trends From Measurement Issues.
      ). 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 (
      • James AH
      • Tapson VF
      • Goldhaber SZ.
      Thrombosis during pregnancy and the postpartum period.
      ), which could partly be attributed to anatomic compression of the left iliac vein by the right iliac artery, exacerbated by the gravid uterus (
      • Ikard RW
      • Ueland K
      • Folse R.
      Lower limb venous dynamics in pregnant 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 (
      • Chan WS
      • Spencer FA
      • Lee AY
      • Chunilal S
      • Douketis JD
      • Rodger M
      • Ginsberg JS.
      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 (
      • Chan WS
      • Spencer FA
      • Lee AY
      • Chunilal S
      • Douketis JD
      • Rodger M
      • Ginsberg JS.
      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 (
      • Elgendy IY
      • Fogerty A
      • Blanco-Molina Á
      • Rosa V
      • Schellong S
      • Skride A
      • Portillo J
      • Lopez-Miguel P
      • Monreal M
      • Weinberg I.
      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 (
      • van Mens TE
      • Scheres LJ
      • de Jong PG
      • Leeflang MM
      • Nijkeuter M
      • Middeldorp S.
      Imaging for the exclusion of pulmonary embolism in pregnancy.
      ). 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 (
      • van der Pol LM
      • Tromeur C
      • Bistervels IM
      • Ni Ainle F
      • van Bemmel T
      • Bertoletti L
      • Couturaud F
      • van Dooren YPA
      • Elias A
      • Faber LM
      • Hofstee HMA
      • van der Hulle T
      • Kruip MJHA
      • Maignan M
      • Mairuhu ATA
      • Middeldorp S
      • Nijkeuter M
      • Roy PM
      • Sanchez O
      • Schmidt J
      • Ten Wolde M
      • Klok FA
      • Huisman MV
      Artemis Study Investigators. Pregnancy-Adapted YEARS Algorithm for Diagnosis of Suspected Pulmonary Embolism.
      ). 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 (
      • Halpenny D
      • Park B
      • Alpert J
      • Latson Jr, L
      • Kim N
      • Babb J
      • Shiau M
      • Ko J.
      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 (
      • Sheen JJ
      • Haramati LB
      • Natenzon A
      • Ma H
      • Tropper P
      • Bader AS
      • Freeman LM
      • Bernstein PS
      Moadel RM. Performance of Low-Dose Perfusion Scintigraphy and CT Pulmonary Angiography for Pulmonary Embolism in Pregnancy.
      ,
      • Mitchell DP
      • Rowan M
      • Loughman E
      • Ridge CA
      • MacMahon PJ.
      Contrast monitoring techniques in CT pulmonary angiography: An important and underappreciated contributor to breast dose.
      ,
      • Shahir K
      • McCrea JM
      • Lozano LA
      • Goodman LR.
      Reduced z-axis technique for CT Pulmonary angiography in pregnancy–validation for practical use and dose reduction.
      ). 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 (
      • van Mens TE
      • Scheres LJ
      • de Jong PG
      • Leeflang MM
      • Nijkeuter M
      • Middeldorp S.
      Imaging for the exclusion of pulmonary embolism in pregnancy.
      ).
      Table 2Signs and symptoms of DVT and PE in pregnancy.
      DVTPE
      Unilateral extremity swellingDyspnea
      TendernessChest pain
      RednessCough
      WarmthTachycardia
      Tachypnea
      Cyanosis
      Note: Two-thirds of pregnant and postpartum women with PE have normal oxygen saturation on presentation
      DVT: deep venous thrombosis; PE: pulmonary embolism

      6. Management of VTE in pregnancy and postpartum

      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 (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ). 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 (
      • van Driel D
      • Wesseling J
      • Sauer PJ
      • van Der Veer E
      • Touwen BC
      • Smrkovsky M.
      In utero exposure to coumarins and cognition at 8 to 14 years old.
      ,
      • Schaefer C
      • Hannemann D
      • Meister R
      • Eléfant E
      • Paulus W
      • Vial T
      • Reuvers M
      • Robert-Gnansia E
      • Arnon J
      • De Santis M
      • Clementi M
      • Rodriguez-Pinilla E
      • Dolivo A
      • Merlob P
      Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study.
      ). 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 (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of 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 (
      • Gould MK
      • Dembitzer AD
      • Doyle RL
      • Hastie TJ
      • Garber AM.
      Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.
      ,
      • Quinlan DJ
      • McQuillan A
      • Eikelboom JW.
      Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials.
      ,
      • Baglin T
      • Barrowcliffe TW
      • Cohen A
      • Greaves M
      British Committee for Standards in Haematology
      Guidelines on the use and monitoring of heparin.
      ). 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 (
      • Bhutia S
      • Wong PF.
      Once versus twice daily low molecular weight heparin for the initial treatment of venous thromboembolism.
      ). 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 (
      • Voke J
      • Keidan J
      • Pavord S
      • Spencer NH
      • Hunt BJ
      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 (
      • Barbour LA
      • Oja JL
      • Schultz LK.
      A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation.
      ,
      • Rey E
      • Rivard GE
      Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin.
      ,
      • Jacobsen AF
      • Qvigstad E
      • Sandset PM.
      Low molecular weight heparin (dalteparin) for the treatment of venous thromboembolism in pregnancy.
      ,
      • McDonnell BP
      • Glennon K
      • McTiernan A
      • O'Connor HD
      • Kirkham C
      • Kevane B
      • Donnelly JC
      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 (
      • Konstantinides SV
      • Meyer G
      • Becattini C
      • Bueno H
      • Geersing GJ
      • Harjola VP
      • Huisman MV
      • Humbert M
      • Jennings CS
      • Jiménez D
      • Kucher N
      • Lang IM
      • Lankeit M
      • Lorusso R
      • Mazzolai L
      • Meneveau N
      • Áinle FN
      • Prandoni P
      • Pruszczyk P
      • Righini M
      • Torbicki A
      • Van Belle E
      • Zamorano JL
      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 (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ). Epidural catheter placement is generally recommended after at least a 24-hour interval between the last dose of greater-than-prophylactic-dose LMWH (
      • Gogarten W
      • Vandermeulen E
      • Van Aken H
      • Kozek S
      • Llau JV
      • Samama CM
      European Society of Anaesthesiology. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology.
      ). 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 (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ).  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 (
      • McLintock C
      • Brighton T
      • Chunilal S
      • Dekker G
      • McDonnell N
      • McRae S
      • Muller P
      • Tran H
      • Walters BN
      • Young L
      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 (
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ).

      6.1 Management of DVT

      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 (
      • Bloom AI
      • Farkas A
      • Kalish Y
      • Elchalal U
      • Spectre G.
      Pharmacomechanical catheter-directed thrombolysis for pregnancy-related iliofemoral deep vein thrombosis.
      ). In the second and third trimesters, however, appropriate precautions including shielding and dose reduction techniques could make this procedure safer (
      • Herrera S
      • Comerota AJ
      • Thakur S
      • Sunderji S
      • DiSalle R
      • Kazanjian SN
      • Assi Z.
      Managing iliofemoral deep venous thrombosis of pregnancy with a strategy of thrombus removal is safe and avoids post-thrombotic morbidity.
      ). 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(
      • Bloom AI
      • Farkas A
      • Kalish Y
      • Elchalal U
      • Spectre G.
      Pharmacomechanical catheter-directed thrombolysis for pregnancy-related iliofemoral deep vein thrombosis.
      ). 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 (
      • Konstantinides SV
      • Meyer G
      • Becattini C
      • Bueno H
      • Geersing GJ
      • Harjola VP
      • Huisman MV
      • Humbert M
      • Jennings CS
      • Jiménez D
      • Kucher N
      • Lang IM
      • Lankeit M
      • Lorusso R
      • Mazzolai L
      • Meneveau N
      • Áinle FN
      • Prandoni P
      • Pruszczyk P
      • Righini M
      • Torbicki A
      • Van Belle E
      • Zamorano JL
      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 (
      • Konstantinides SV
      • Meyer G
      • Becattini C
      • Bueno H
      • Geersing GJ
      • Harjola VP
      • Huisman MV
      • Humbert M
      • Jennings CS
      • Jiménez D
      • Kucher N
      • Lang IM
      • Lankeit M
      • Lorusso R
      • Mazzolai L
      • Meneveau N
      • Áinle FN
      • Prandoni P
      • Pruszczyk P
      • Righini M
      • Torbicki A
      • Van Belle E
      • Zamorano JL
      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).
      ). These patients can be managed as outpatient, and do not require hospital admission (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ). Acute high-risk PE, characterized by hemodynamic instability with end-organ hypoperfusion, is rare during pregnancy but potentially life-threatening and requires hospitalization (
      • Konstantinides SV
      • Meyer G
      • Becattini C
      • Bueno H
      • Geersing GJ
      • Harjola VP
      • Huisman MV
      • Humbert M
      • Jennings CS
      • Jiménez D
      • Kucher N
      • Lang IM
      • Lankeit M
      • Lorusso R
      • Mazzolai L
      • Meneveau N
      • Áinle FN
      • Prandoni P
      • Pruszczyk P
      • Righini M
      • Torbicki A
      • Van Belle E
      • Zamorano JL
      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 (
      • 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.
      ). 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 (
      • 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.
      ). 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 (
      • Konstantinides SV
      • Meyer G
      • Becattini C
      • Bueno H
      • Geersing GJ
      • Harjola VP
      • Huisman MV
      • Humbert M
      • Jennings CS
      • Jiménez D
      • Kucher N
      • Lang IM
      • Lankeit M
      • Lorusso R
      • Mazzolai L
      • Meneveau N
      • Áinle FN
      • Prandoni P
      • Pruszczyk P
      • Righini M
      • Torbicki A
      • Van Belle E
      • Zamorano JL
      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).
      ).
      Fig. 3:
      Fig. 3Management of acute pulmonary embolism in pregnancy.
      Demonstrates the scheme for early risk stratification and management of acute pulmonary embolism.
      PE: pulmonary embolism; IVC filter: inferior vena cava filter.
      *IVC filter could be considered in women with pulmonary embolism without evidence of DVT, who are not candidate for systemic anticoagulation.
      **History of malignancy, congestive heart failure, chronic interstitial or obstructive lung disease.
      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 (
      • Elgendy IY
      • Fogerty A
      • Blanco-Molina Á
      • Rosa V
      • Schellong S
      • Skride A
      • Portillo J
      • Lopez-Miguel P
      • Monreal M
      • Weinberg I.
      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 (
      • Harris SA
      • Velineni R
      • Davies AH.
      Inferior Vena Cava Filters in Pregnancy: A Systematic Review.
      ). 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 (
      • Brill-Edwards P
      • Ginsberg JS
      • Gent M
      • Hirsh J
      • Burrows R
      • Kearon C
      • Geerts W
      • Kovacs M
      • Weitz JI
      • Robinson KS
      • Whittom R
      • Couture G
      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 (
      • Pabinger I
      • Grafenhofer H
      • Kyrle PA
      • Quehenberger P
      • Mannhalter C
      • Lechner K
      • Kaider A.
      Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism.
      ). 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 (
      • Lindqvist PG
      • Bremme K
      • Hellgren M
      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.
      ).
      Although pharmacological therapy may reduce the incidence and recurrence of VTE during pregnancy and the postpartum period (
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      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 (
      • Greer IA
      • Nelson-Piercy C.
      Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.
      ). 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 (
      • Gould MK
      • Dembitzer AD
      • Doyle RL
      • Hastie TJ
      • Garber AM.
      Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.
      ,
      • Quinlan DJ
      • McQuillan A
      • Eikelboom JW.
      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 (
      • Stephenson ML
      • Serra AE
      • Neeper JM
      • Caballero DC
      • McNulty J.
      A randomized controlled trial of differing doses of postcesarean enoxaparin thromboprophylaxis in obese women.
      ,
      • Knol HM
      • Schultinge L
      • Veeger NJ
      • Kluin-Nelemans HC
      • Erwich JJ
      • Meijer K
      The risk of postpartum hemorrhage in women using high dose of low-molecular-weight heparins during pregnancy.
      ,
      • Roshani S
      • Cohn DM
      • Stehouwer AC
      • Wolf H
      • van der Post JA
      • Büller HR
      • Kamphuisen PW
      • Middeldorp S.
      Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular-weight heparin: results of a retrospective cohort study.
      ). 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 (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      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.
      ).
      Pharmacologic thromboprophylaxis is usually reserved for a select population of pregnant women who are considered at high risk for VTE (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      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 (
      • Rodger M.
      Pregnancy and venous thromboembolism: 'TIPPS' for risk stratification.
      ). 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 (
      • White RH
      • Chan WS
      • Zhou H
      • Ginsberg JS.
      Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism.
      ,
      • De Stefano V
      • Martinelli I
      • Rossi E
      • Battaglioli T
      • Za T
      • Mannuccio Mannucci P
      • Leone G
      The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis.
      ). Among pregnant women with no or 1 risk factor (excluding a known thrombophilia), antepartum and postpartum pharmacological thromboprophylaxis is not generally recommended (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ). 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 (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      ).
      The recommendations for pharmacological thromboprophylaxis in specific thrombophilia disorders are subject to variability in different guidelines (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ,
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      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.
      American Society of Hematology (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      )
      American College of Chest Physicians (
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      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 (
      American College of Obstetricians
      and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in Pregnancy.
      )
      Homozygosity for factor V Leiden or prothrombin gene mutation
      Antepartum:

      +ve FH - prophylaxis

      -ve FH – prophylaxis for FVL, while surveillance for prothrombin gene mutation

      Antepartum:

      +ve FH - prophylaxis

      -ve FH - surveillance
      Antepartum:

      +ve FH - prophylaxis

      -ve FH - prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - prophylaxis

      Postpartum:

      +ve FH – Therapeutic anticoagulation

      -ve FH – Therapeutic anticoagulation

      Heterozygosity for factor V Leiden or prothrombin gene mutation
      Antepartum:

      +ve FH - No prophylaxis

      -ve FH - No prophylaxis

      Antepartum:

      +ve FH - surveillance

      -ve FH - surveillance
      Antepartum:

      +ve FH - Either surveillance or prophylaxis

      -ve FH - Either surveillance or prophylaxis

      Postpartum:

      +ve FH - No prophylaxis

      -ve FH - No prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - surveillance
      Postpartum:

      +ve FH - Either surveillance or anticoagulation

      -ve FH - Either surveillance or anticoagulation

      Protein C/S deficiency
      Antepartum:

      +ve FH - No prophylaxis

      -ve FH - No prophylaxis

      Antepartum:

      +ve FH - surveillance

      -ve FH - surveillance
      Antepartum:

      +ve FH - Either surveillance or prophylaxis

      -ve FH - Either surveillance or prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - No prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - surveillance
      Postpartum:

      +ve FH - Either surveillance or anticoagulation

      -ve FH - Either surveillance or anticoagulation

      Antithrombin deficiency
      Antepartum:

      +ve FH - Prophylaxis

      -ve FH - No prophylaxis

      Antepartum:

      +ve FH - surveillance

      -ve FH - surveillance
      Antepartum:

      +ve FH - prophylaxis

      -ve FH - prophylaxis

      Postpartum:

      +ve FH - Prophylaxis

      -ve FH - No prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - surveillance
      Postpartum:

      +ve FH – Therapeutic anticoagulation

      -ve FH – Therapeutic anticoagulation

      Compound heterozygosity
      Antepartum:

      +ve FH - prophylaxis

      -ve FH - prophylaxis

      Antepartum:

      +ve FH - surveillance

      -ve FH - surveillance
      Antepartum:

      +ve FH - prophylaxis

      -ve FH - prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - prophylaxis

      Postpartum:

      +ve FH - prophylaxis

      -ve FH - surveillance
      Postpartum:

      +ve FH – Therapeutic anticoagulation

      -ve FH – Therapeutic anticoagulation

      +ve FH: positive family history for venous thromboembolism; -ve FH: negative family history for venous thromboembolism; FVL: factor V Leiden
      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 (
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      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 (
      • Empson M
      • Lassere M
      • Craig JC
      • Scott JR.
      Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials.
      ). 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 (
      • Bates SM
      • Greer IA
      • Middeldorp S
      • Veenstra DL
      • Prabulos AM
      • Vandvik PO
      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.
      Increased venous thrombosis incidence in pregnancies after in vitro fertilization.
      ,

      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.

      ). Higher risks of VTE have been reported among patients with severe ovarian hyperstimulation syndrome particularly those requiring hospitalization (
      • Rova K
      • Passmark H
      • Lindqvist PG.
      Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles.
      ,
      • Abramov Y
      • Elchalal U
      • Schenker JG.
      Obstetric outcome of in vitro fertilized pregnancies complicated by severe ovarian hyperstimulation syndrome: a multicenter study.
      ,
      • Serour GI
      • Aboulghar M
      • Mansour R
      • Sattar MA
      • Amin Y
      • Aboulghar H.
      Complications of medically assisted conception in 3,500 cycles.
      ). Prophylactic anticoagulation is not recommended except if the patient develops severe ovarian hyperstimulation syndrome (
      • Bates SM
      • Rajasekhar A
      • Middeldorp S
      • McLintock C
      • Rodger MA
      • James AH
      • Vazquez SR
      • Greer IA
      • Riva JJ
      • Bhatt M
      • Schwab N
      • Barrett D
      • LaHaye A
      • Rochwerg B.
      American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy.
      ).

      8. Future Directions

      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: venous thromboembolism

      9. Conclusions

      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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      • Pregnancy-related venous thromboembolism: Progress but questions remain
        European Journal of Internal MedicineVol. 97
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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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