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Venous Thromboembolism and Antithrombotic Therapy in Pregnancy

      Abstract

      Objective

      To present an approach, based on current evidence, for the diagnosis, treatment, and thromboprophylaxis of venous thromboembolism in pregnancy and postpartum.

      Evidence

      Published literature was retrieved through searches of PubMed, Medline, CINAHL, and The Cochrane Library from November 2011 to July 2013 using appropriate controlled vocabulary (e.g. pregnancy, venous thromboembolism, deep vein thrombosis, pulmonary embolism, pulmonary thrombosis) and key words (e.g., maternal morbidity, pregnancy complications, thromboprophylaxis, antithrombotic therapy). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English or French. There were no date restrictions. Grey (unpublished) literature was identified through searching the websites of clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.

      Values

      The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1).

      Key Words

      ABBREVIATIONS

      APLS
      antiphospholipid syndrome
      aPTT
      activated partial thromboplastin time
      ART
      assisted reproductive technology
      AT
      antithrombin
      ASA
      acetylsalicylic acid
      ASRA
      American Society of Regional Anesthesia
      BMI
      body mass index
      CT
      computed tomography
      CTA
      CT angiography
      CUS
      compression ultrasound
      CVT
      cerebral venous thrombosis
      DVT
      deep vein thrombosis
      FVL
      factor V Leiden
      HIT
      heparin-induced thrombocytopenia
      IUGR
      intrauterine growth restriction
      LDA
      low-dose ASA
      LMWH
      low molecular weight heparin
      MRI
      magnetic resonance imaging
      NSAID
      non-steroidal anti-inflammatory drug
      OHSS
      ovarian hyperstimulation syndrome
      OVT
      ovarian vein thrombosis
      PGM
      prothrombin gene mutation 20210A
      PC
      protein C
      PE
      pulmonary embolism
      PS
      protein S
      SGA
      small for gestational age
      SLE
      systemic lupus erythematosus
      ST
      superficial thrombophlebitis
      UH
      unfractionated heparin
      VQ
      ventilation/perfusion
      VTE
      venous thromboembolism

      Recommendations

      • 1.
        Objective testing is required following clinical suspicion of deep vein thrombosis or pulmonary embolism. (II-2A)
      • 2.
        For the diagnosis of deep vein thrombosis, ultrasonography is recommended, and should be repeated at least once over 7 days if the initial study is negative. For each examination, the entire length of the venous system from the external iliac to the popliteal vein must be visualized and compression manoeuvres performed from the femoral to the popliteal vein. (II-2B)
      • 3.
        For the diagnosis of pulmonary embolism, either ventilation-perfusion scan or computed tomographic angiography can be used. (II-2A) In pregnant women, a ventilation-perfusion scan is the preferred test. (III-B)
      • 4.
        Neither D-dimer alone nor clinical prediction rules should be used to rule out venous thromboembolism in pregnant women without objective testing. (III-D)
      • 5.
        Pregnant women diagnosed with acute venous thromboembolism should be hospitalized or followed closely as outpatients for the first 2 weeks after the initial diagnosis. (III-C)
      • 6.
        Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for the treatment of venous thromboembolism in pregnancy. (II-2A)
      • 7.
        Heparin-induced thrombocytopenia in pregnant women is extremely rare. Consultation with a hematologist or thrombosis specialist is recommended to consider the use of heparanoids for treatment of venous thromboembolism if it occurs. (II-3B)
      • 8.
        Vitamin K antagonists should only be considered in exceptional circumstances for the treatment of venous thromboembolism in pregnancy. (II-2A)
      • 9.
        We recommend against the use of oral Xa inhibitors and oral direct thrombin inhibitors for the treatment of venous thromboembolism in pregnancy. (III-D)
      • 10.
        For the treatment of acute venous thromboembolism in pregnancy we recommend adhering to the manufacturer's recommended dosing for individual low molecular weight heparins based on the woman's current weight. (II-1A) Low molecular weight heparin can be administered once or twice a day depending on the agent selected. (III-C)
      • 11.
        For pregnant women initiated on therapeutic low molecular weight heparin, baseline platelet counts should be done and repeated a week later to screen for heparin-induced thrombocytopenia. (III-C)
      • 12.
        For pregnant women with an acute venous thromboembolism we recommend therapeutic anticoagulation for a minimum of 3 months. (I-A)
      • 13.
        Following initial treatment, anticoagulation intensity can be decreased to intermediate or prophylactic dose for the remainder of the pregnancy and for at least 6 weeks postpartum. (III-C)
      • 14.
        In pregnant women with acute proximal leg deep vein thrombosis, the use of graded compression stockings can be considered for relief of symptoms. (III-C)
      • 15.
        Thrombolytic therapy in pregnancy should only be considered in limb-threatening deep vein thrombosis or massive pulmonary embolism. (III-C)
      • 16.
        Vena cava filters should only be used in pregnant women with acute pulmonary embolism or deep vein thrombosis and contraindications to anticoagulation. (III-C)
      • 17.
        Computed tomographic venography and/or magnetic resonance imaging should be performed to rule out cerebral venous thrombosis if suspected. (I-C)
      • 18.
        Therapeutic dose anticoagulation should be initiated for confirmed cerebral venous thrombosis. (II-2A)
      • 19.
        Thromboprophylaxis should be considered in future pregnancies following a cerebral venous thrombosis. (II-1C)
      • 20.
        For superficial thrombophlebitis, compression ultrasound should be performed to exclude deep vein thrombosis (II-2A), and it should be repeated if proximal extension is suspected based on worsening phlebitis. (III-C)
      • 21.
        Prophylactic or intermediate dose low molecular weight heparin for 1 to 6 weeks is recommended for women with bilateral superficial thrombophlebitis, for very symptomatic women, and for superficial thrombophlebitis located ≤5 cm from the deep venous system (saphenofemoral and saphenopopliteal junctions) or affecting5 cm of vein. (I-A)
      • 22.
        Observation alone is recommended in women with superficial thrombophlebitis at low risk of deep vein thrombosis and for those who do not require symptom control. Clinical follow-up of these women should occur within 7 to 10 days, with a repeat compression ultrasound within one week. (I-A)
      • 23.
        Computed tomography and/or magnetic resonance imaging (with or without angiography) are the definitive imaging modalities to rule out ovarian vein thrombosis. (II-2A)
      • 24.
        For confirmed ovarian vein thrombosis, we recommend parenteral broad-spectrum antibiotics, continued for at least 48 hours after defervescence and clinical improvement. (II-2A) Longer antibiotic therapy is necessary for septicemia or complicated infections. (III-C)
      • 25.
        For confirmed ovarian vein thrombosis, therapeutic dose anticoagulation could be considered for 1 to 3 months. (III-C)
      • 26.
        Routine screening for all inherited thrombophilias in all women with a first episode of venous thromboembolism diagnosed in pregnancy is not indicated. (III-C)
      • 27.
        Testing for protein S, protein C, and antithrombin deficiencies is indicated following a venous thromboembolism in pregnancy if there is a family history of these particular thrombophilias, or if thrombosis occurs in an unusual site. (III-C)
      • 28.
        Testing for antiphospholipid antibodies is indicated if the results would affect the duration of anticoagulation. (III-C)
      • 29.
        Individual risk assessment for venous thromboembolism should be performed prior to all pregnancies, once pregnancy is achieved, and repeated throughout pregnancy as new clinical situations arise. The woman's preferences and values should be taken into account when considering the use of antepartum thromboprophylaxis. (III-B)
      • 30.
        Women at increased risk should be advised of the symptoms and signs of venous thromboembolism. (III-B)
      • 31.
        Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for antepartum thromboprophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer's recommendation. (III-C)
      • 32.
        Routine anti-Xa medication and platelet-level monitoring are not recommended when a patient is on a prophylactic dose of thromboprophylaxis. (II-2E)
      • 33.
        We recommend therapeutic thromboprophylaxis during pregnancy in the following situations:
        • a.
          long-term therapeutic anticoagulation used prior to pregnancy for a persistent indication; (III-B)
        • b.
          personal history of multiple previous venous thromboembolism. (III-B)
      • 34.
        We recommend intermediate or therapeutic thromboprophylaxis during pregnancy in the following situation:
        • a.
          personal history of a previous venous thromboembolism and a high-risk thrombophilia (antithrombin deficiency, antiphospholipid syndrome) not previously on anticoagulation. (III-B)
      • 35.
        We recommend prophylactic dose thromboprophylaxis during pregnancy in the following situations (absolute risk>1%):
        • a.
          personal history of a previous unprovoked venous thromboembolism; (II-2A)
        • b.
          personal history of a previous venous thromboembolism related to oral contraceptives or pregnancy; (II-2A)
        • c.
          personal history of a previous provoked venous thromboembolism and any low risk thrombophilia; (I-A)
        • d.
          asymptomatic homozygous factor V Leiden; (II-2A)
        • e.
          asymptomatic homozygous prothrombin gene mutation 20210A; (III-B)
        • f.
          asymptomatic combined thrombophilia; (III-B)
        • g.
          asymptomatic antithrombin deficiency; (III-B)
        • h.
          non-obstetrical surgery during pregnancy, with the duration of thromboprophylaxis being procedure- and patient- dependent; (III-B)
        • i.
          strict antepartum bedrest for >7 days in a woman with a body mass index of>25 kg/m2 at her first antenatal visit. (II-2B)
      • 36.
        Antepartum thromboprophylaxis for isolated pregnancy-related risk factors is not recommended. (III-E)
      • 37.
        Antepartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors where the overall absolute risk of venous thromboembolism is estimated to be>1%, especially in women admitted to hospital for bed rest. (II-2B)
      • 38.
        Routine thromboprophylaxis is not required for all women undergoing ovulation induction. (III-C)
      • 39.
        If severe ovarian hyperstimulation syndrome occurs with assisted reproductive technology, we recommend thromboprophylaxis with low molecular weight heparin for at least 8 to 12 weeks after resolution of the syndrome. (III-B)
      • 40.
        Thromboprophylaxis with low molecular weight heparin should be considered for any women at increased risk for venous thromboembolism undergoing assisted reproductive technology at the time of ovarian stimulation. (III-B)
      • 41.
        Women who develop a venous thromboembolism in association with the use of assisted reproductive technology but who do not conceive in that cycle should be treated with therapeutic anticoagulation for a minimum of 3 months. (II-3A) Those who conceive in that assisted reproductive technology cycle should be treated as per recommendations 12 and 13 for acute venous thromboembolism in pregnancy. (I-A, III-C)
      • 42.
        Women on prophylactic dose, intermediate dose, or therapeutic anticoagulation should have a discussion about options for analgesia/anaesthesia prior to delivery. (III-B)
      • 43.
        Switching from thromboprophylactic low molecular weight heparin to a prophylactic dose of unfractionated heparin at term (37 weeks) may be considered to allow for more options with respect to labour analgesia. (III-L)
      • 44.
        Discontinue prophylactic or intermediate dose low molecular weight heparin or unfractionated heparin upon the onset of spontaneous labour or the day prior to a planned induction of labour or Caesarean section. (II-3B)
      • 45.
        A recent platelet count should be available on admission in labour or before Caesarean delivery in women who have been, or are, on anticoagulants. (III-B)
      • 46.
        For women on low molecular weight heparin, neuraxial anaesthesia can be administered as a:
        • a.
          prophylactic dose: a minimum of 10 to 12 hours after the last dose; (III-B)
        • b.
          therapeutic dose: after 24 hours since the last dose. (III-B)
      • 47.
        For women on unfractionated heparin, neuraxial anaesthesia can be administered as a:
        • a.
          prophylactic dose (maximum 10 000 U/day): after no delay; (III-B)
        • b.
          therapeutic intravenous infusion: at least 4 hours after stopping the infusion and when the activated partial thromboplastin time is normal; (III-B)
        • c.
          therapeutic subcutaneous unfractionated heparin: when the activated partial thromboplastin time is normal. This may be 12 hours or longer after the last injection. (III-B)
      • 48.
        Neuraxial anaesthesia must be avoided in a woman who is fully anticoagulated or in whom there is evidence of altered coagulation. (II-3A)
      • 49.
        Removal of a neuraxial catheter left in situ postpartum should only be done 4, 10 to 12, or 24 hours following the administration of prophylactic dose unfractionated heparin (maximum 10 000 U/day), prophylactic low molecular weight heparin (single daily dose), or therapeutic dose low molecular weight heparin, respectively, or in the case of therapeutic unfractionated heparin, when the activated partial thromboplastin time is normal. (II-3B)
      • 50.
        Prophylactic dose low molecular weight heparin (single daily dose) may be started or restarted 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B)
      • 51.
        Therapeutic low molecular weight heparin may be started or restarted at least 24 hours after a single injection neuraxial block and a minimum of 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B)
      • 52.
        Subcutaneous unfractionated heparin may be started or restarted at least 1 hour after a single injection neuraxial block, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B)
      • 53.
        Do not administer antiplatelet agents (acetylsalicylic acid or nonsteroidal anti-inflammatory drugs) concomitantly with heparin if a neuraxial catheter is left in situ postpartum. (III-D)
      • 54.
        Women on therapeutic anticoagulation who have received neuraxial anesthesia should be monitored closely for the development of a spinal hematoma. (III-B)
      • 55.
        Universal postpartum thromboprophylaxis is not recommended. (III-D)
      • 56.
        Assess women for increased risk of postpartum venous thromboembolism based on antepartum, intrapartum, and postpartum risk factors after every delivery and repeat as new clinical situations arise. (II-2B)
      • 57.
        Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for postpartum thromboprophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer's recommendation. (III-C)
      • 58.
        Pharmacologic thromboprophylaxis postpartum is recommended in the following situations:
      • Any 1 of the following risk factors (each with an absolute risk of venous thromboembolism>1%):
        • a.
          history of any prior venous thromboembolism; (II-2A)
        • b.
          any high-risk thrombophilia: antiphospholipid syndrome, antithrombin deficiency, homozygous factor V Leiden or prothrombin gene mutation 20210A, or combined thrombophilia; (II-2B)
        • c.
          strict bedrest prior to delivery for 7 days or more; (II-2B)
        • d.
          peripartum or postpartum blood loss of>1 litre or blood product replacement, and concurrent postpartum surgery; (II-2B)
        • e.
          peripartum/postpartum infection. (II-2B)
      • 59.
        Postpartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors when the overall absolute risk is estimated to be greater than 1% drawn from the following groupings:
        • a.
          any 2 of the following risk factors (each with an absolute risk of venous thromboembolism<1% in isolation):
          • i.
            body mass index30 kg/m2 at first antepartum visit; (II-2B)
          • ii.
            smoking>10 cigarettes/day antepartum; (II-2B)
          • iii.
            preeclampsia; (II-2B)
          • iv.
            intrauterine growth restriction; (II-2B)
          • v.
            placenta previa; (II-2B)
          • vi.
            emergency Caesarean section; (II-2B)
          • vii.
            peripartum or postpartum blood loss of>1 litre or blood product replacement; (II-2B)
          • viii.
            any low risk thrombophilia: PC or PS deficiency, heterozygous factor V Leiden, or prothrombin gene mutation 20210A; (III-B)
          • ix.
            maternal cardiac disease, SLE, sickle cell disease, inflammatory bowel disease, varicose veins, gestational diabetes; (III-B)
          • x.
            preterm delivery; (III-B)
          • xi.
            stillbirth. (III-B)
        • b.
          Any 3 or more of the following risk factors (each with an absolute risk of venous thromboembolism<1%):
          • i.
            age>35 years; (II-2B)
          • ii.
            parity2; (II-2B)
          • iii.
            any assisted reproductive technology; (II-2B)
          • iv.
            multiple pregnancy; (II-2B)
          • v.
            placental abruption; (II-2B)
          • vi.
            premature rupture of membranes; (II-2B)
          • vii.
            elective Caesarean section; (II-2B)
          • viii.
            maternal cancer. (III-B)
      • 60.
        Intermittent or sequential pneumatic compression devices are alternatives in women when heparin is contraindicated postpartum. When the risk of postpartum venous thromboembolism is high they may be used in combination with low molecular weight heparin or unfractionated heparin. (III-B)
      • 61.
        Women with ongoing and persistent risk factors should receive postpartum thromboprophylaxis for a minimum of 6 weeks postpartum. (II-3B)
      • 62.
        Women with transient antepartum or intrapartum risk factors should receive postpartum thromboprophylaxis until discharged from hospital or up to 2 weeks postpartum. (III-C)
      • 63.
        Universal screening for thrombophilias in women experiencing adverse pregnancy outcomes (severe preeclampsia, intrauterine growth restriction, stillbirth) is not indicated. (II-2D)
      • 64.
        Women with recurrent miscarriage or late pregnancy loss should be screened for antiphospholipid syndrome. (I-B)
      • 65.
        Low-dose acetylsalicylic acid or low-dose acetylsalicylic acid plus low molecular weight heparin is recommended in pregnancy in women with confirmed antiphospholipid syndrome. (I-C)
      • 66.
        Low-dose acetylsalicylic acid plus low molecular weight heparin is not recommended for women with a history of recurrent miscarriage in the absence of confirmed antiphospholipid syndrome. (I-E)
      • 67.
        Low molecular weight heparin should not be used routinely to reduce the risk of recurrent placenta-mediated complications in women with or without thrombophilia (excluding antiphospholipid syndrome). (I-C)

      INTRODUCTION

      This guideline summarizes the available data and the quality of the evidence to provide practical approaches to the diagnosis, management, and prevention of VTE in pregnancy. VTE remains an important cause of maternal morbidity and mortality in Canada with an overall incidence of DVT and PE of 12.1 per 10 000 and 5.4 per 10 000 pregnancies, respectively.
      • Liu S.
      • Rouleau J.
      • Joseph K.S.
      • Sauve R.
      • Liston R.
      • Young D.
      • et al.
      Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada.
      VTE occurs at a rate of 5.4 per 10 000 antepartum, 7.2 per 10 000 peripartum, and 4.3 per 10 000 pregnancies postpartum.
      • Liu S.
      • Rouleau J.
      • Joseph K.S.
      • Sauve R.
      • Liston R.
      • Young D.
      • et al.
      Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada.
      These rates are consistent with published literature from around the world.
      • Lindqvist P.
      • Dahlback B.
      • Marsal K.
      Thrombotic risk during pregnancy: a population study.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study.
      • Sultan A.A.
      • Tata L.
      • West J.
      • Fiaschi L.
      • Fleming K.
      • Nelson-Piercy C.
      • et al.
      Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom.
      The first and second trimesters of pregnancy convey similar risks for DVT, with a higher risk in the third trimester and the first 3 weeks postpartum.
      • Sultan A.A.
      • West J.
      • Tata L.J.
      • Fleming K.
      • Nelson-Piercy C.
      • Grainge M.J.
      Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study.
      • Virkus R.A.
      • Lokkegaard E.C.L.
      • Bergholt T.
      • Mogensen U.
      • Langhoff-Roos J.
      • Lidegaard O.
      Venous thromboembolism in pregnant and puerperal women in Denmark 1995-2005.
      PE occurs more commonly postpartum, decreasing in incidence after the first 6 weeks.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study.
      • Heit J.A.
      • Kobbervig C.E.
      • James A.H.
      • Petterson T.M.
      • Bailey K.R.
      • Melton L.J.
      Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study.
      This guideline sequentially reviews key components in reducing the risk VTE in pregnancy, which include accurate diagnosis and treatment of DVT and PE, antepartum thromboprophylaxis in appropriate patients, peripartum management of anticoagulants, and postpartum thromboprophylaxis, and concludes with a discussion of the use of heparin to prevent adverse pregnancy outcomes.
      Making decisions about the management of individual patients can be challenging and complex. Wherever possible, this guideline attempts to summarize and organize the existing evidence that supports the recommendations, and it is meant to be complementary to other international guidelines on this topic.
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      • Jaeschke R.
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      • Goodacre S.
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      • Stevenson M.D.
      • et al.
      Diagnosis of DVT. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      • 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.
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      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      • Nelson-Piercy C.
      • MacCallum P.
      • Mackillop L.
      Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top guideline no. 37a.
      • Greer I.A.
      • Thomson A.J.
      The acute management of thrombosis and embolism during pregnancy and the puerperium. Green-top guideline no. 37b.
      • McLintock C.
      • Brighton T.
      • Chunilal S.
      • Dekker G.
      • McDonnell N.
      • McRae S.
      • et al.
      Councils of the Society of Obstetric Medicine of Australia and New Zealand; Australasian Society of Thrombosis and Haemostasis. Recommendations for the prevention of pregnancy- associated venous thromboembolism.
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      • McRae S.
      • et al.
      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.
      • Lindqvist P.G.
      • Hellgren M.
      Obstetric thromboprophylaxis: the Swedish guidelines.

      ACUTE VENOUS THROMBOEMBOLISM IN PREGNANCY

      Due to hormonal influences on vascular tone and compressive effects on veins by the enlarging uterus, DVT in pregnancy generally presents in the lower extremities, with a predisposition for the left leg (70 to 80%).
      • Macklon N.S.
      • Greer I.A.
      • Bowman A.W.
      An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy.
      • Ray J.G.
      • Chan W.S.
      Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation.
      In contrast to their presentation in non-pregnant patients, DVTs are often isolated to the iliac and/or femoral vein during pregnancy (61%).
      • Chan W.S.
      • Spencer F.A.
      • Ginsberg J.S.
      Anatomic distribution of deep vein thrombosis in pregnancy.
      Consequently diagnostic approaches advocated for use in non-pregnant patients require modification in pregnancy.
      • Bates S.M.
      • Jaeschke R.
      • Stevens S.M.
      • Goodacre S.
      • Wells P.S.
      • Stevenson M.D.
      • et al.
      Diagnosis of DVT. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.

      Diagnosis of VTE in Pregnancy

      In non-pregnant patients, diagnostic approaches for VTE use a combination of validated structured clinical prediction rules with or without the use of D-dimer testing, followed by objective testing with CUS.
      • Bates S.M.
      • Jaeschke R.
      • Stevens S.M.
      • Goodacre S.
      • Wells P.S.
      • Stevenson M.D.
      • et al.
      Diagnosis of DVT. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      Extrapolating the same approach to pregnancy is difficult because:
      • 1.
        structured prediction rules have not been validated in pregnant women,
      • 2.
        the anatomic presentation of lower extremity DVT in pregnant women could affect the sensitivity of CUS,
        • Chan W.S.
        • Spencer F.A.
        • Ginsberg J.S.
        Anatomic distribution of deep vein thrombosis in pregnancy.
        and
      • 3.
        current validated D-dimer level cut-off points are of limited utility.
        • To M.S.
        • Hunt B.J.
        • Nelson-Piercy C.
        A negative D-dimer does not exclude venous thromboembolism in pregnancy.
        • Damodaram M.
        • Kaladindi M.
        • Luckit J.
        • Yoong W.
        D-dimers as a screening test for venous thromboembolism in pregnancy: is it of any use?.
      The potential use of a pregnancy-specific structured prediction rule and pregnancy-specific D-dimer thresholds has been reported,
      • 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.
      • 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?.
      • Chan W.S.
      • Lee A.
      • Spencer F.A.
      • Chunilal S.
      • Crowther M.
      • Wu W.
      • et al.
      D-dimer testing in pregnant patients: towards determining the next ‘level’ in the diagnosis of deep vein thrombosis.
      but currently neither test should be used alone or in combination to diagnose or exclude VTE without further validation studies.
      Our recommended diagnostic algorithm for DVT in pregnancy is shown in Figure 1. When a pregnant woman presents with a suspected DVT, she should undergo an ultrasound including direct visualization of the entire proximal venous system from the iliac to the popliteal vein.
      • Le Gal G.
      • Kercret G.
      • Ben Yahmed K.
      • Bressollette L.
      • Robert-Ebadi H.
      • Riberdy L.
      • et al.
      EDVIGE Study Group
      Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: a prospective study.
      Doppler studies should be performed at the level of the iliac vein to ensure that flow is present. Compression manoeuvers should be performed along the entire venous system from the femoral to the popliteal vein. The sensitivity and negative predictive value of this method are 90.9% (95% CI 69.4 to 98.4) and 98.9% (95% CI 95.5 to 99.8), respectively.
      • Le Gal G.
      • Kercret G.
      • Ben Yahmed K.
      • Bressollette L.
      • Robert-Ebadi H.
      • Riberdy L.
      • et al.
      EDVIGE Study Group
      Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: a prospective study.
      Published evidence is currently insufficient to support the safety of performing a single ultrasound examination in pregnant women with suspected DVT. Hence, we would recommend repeat testing with CUS and Doppler imaging as above at least once again over the next 7 days if the initial study is negative. If isolated iliac vein obstruction (i.e. absence of flow) is suspected on Doppler examination, two options are available:
      • 1.
        institute therapeutic anticoagulation followed by repeat CUS in 2 to 3 days, or
      • 2.
        proceed with MRI.
      Figure thumbnail gr1
      Figure 1Algorithm for the diagnosis of deep venous thrombosis in pregnant patients
      The option chosen depends on patient preference, availability of expertise, and access to imaging. The specificity and sensitivity of MRI and the specific technique used to diagnose DVT in pregnancy remains uncertain.
      • Fraser D.G.
      • Moody A.R.
      • Morgan P.S.
      • Martel A.L.
      • Davidson I.
      Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging.
      • Sampson F.C.
      • Goodacre S.W.
      • Thomas S.M.
      • van Beek E.J.
      The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis.
      When PE is suspected clinically, definitive diagnosis requires diagnostic imaging. Several factors should be considered in the choice of VQ scan or CTA:
      • 1.
        the maternal and fetal risks associated with the tests (radiation and contrast agent),
      • 2.
        the sensitivity of the tests, and
      • 3.
        their availability.
      For both VQ scan and CTA the calculated radiation risk to the fetus is low, with levels below the threshold of 50 mGy for subsequent childhood malignancy.
      • Ginsberg J.S.
      • Hirsh J.
      • Rainbow R.J.
      • Coates G.
      Risks to the fetus of radiologic procedures used in the diagnosis of maternal thromboembolic disease.
      • Doll R.
      • Wakefield R.
      Risk of childhood cancer from fetal radiation.
      • Hurwitz L.M.
      • Yoshizumi T.
      • Reiman R.E.
      • Goodman P.C.
      • Paulson E.K.
      • Frush D.P.
      • et al.
      Radiation dose to the fetus from body MDCT during early gestation.
      The calculated minimum radiation dose to each breast for an average 60 kg woman is 20 to 35 mGy from CTA and 0.28 mGy from VQ scan.
      • Cook J.V.
      • Kyriou J.
      Radiation from CT and perfusion scanning in pregnancy.
      • Parker M.S.
      • Hui F.K.
      • Camacho M.A.
      • Chung J.K.
      • Broga D.W.
      • Sethi N.N.
      Female breast radiation exposure during CT pulmonary angiography.
      While little is known about the long-term effects of radiation exposure to breast tissue during pregnancy, there are data linking imaging procedures to an increased risk of breast cancer.
      • Berrington de Gonzalez A.
      • Darby S.
      Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries.
      The iodinated contrast agent required for computed tomographic angiography to diagnosis PE crosses the placenta and can theoretically result in fetal or neonatal hypothyroidism. However, this risk was not significant in an observational study of over 300 pregnancies.
      • Bourjeily G.
      • Chalhoub M.
      • Phornphutkul C.
      • Alleyne T.C.
      • Woodfield C.A.
      • Chen K.K.
      Neonatal thyroid function: effect of a single exposure to iodinated contrast medium in utero.
      In pregnancy the observed sensitivity and negative predictive values of CTA and VQ scan appears to be high, using clinical outcome as a surrogate measure.
      • Chan W.S.
      • Ray J.G.
      • Murray S.
      • Coady G.E.
      • Coates G.
      • Ginsberg J.S.
      Suspected pulmonary embolism in pregnancy: clinical presentation, results of lung scanning, and subsequent maternal and pediatric outcomes.
      • Scarsbrook A.F.
      • Bradley K.M.
      • Gleeson F.V.
      Perfusion scintigraphy: diagnostic utility in pregnant women with suspected pulmonary embolic disease.
      • Cahill A.G.
      • Stout M.J.
      • Macones G.A.
      • Bhalla S.
      Diagnosing pulmonary embolism in pregnancy using computed-tomographic angiography or ventilation-perfusion.
      • Shahir K.
      • Goodman L.R.
      • Tali A.
      • Thorsen K.M.
      • Hellman R.S.
      Pulmonary embolism in pregnancy: CT pulmonary angiography versus perfusion scanning.
      • Bourjeily G.
      • Khalil H.
      • Raker C.
      • Martin S.
      • Auger P.
      • Chalhoub M.
      • et al.
      Outcomes of negative multidetector computed tomography with pulmonary angiography in pregnant women suspected of pulmonary embolism.
      The specificity of a CTA in pregnancy cannot be ascertained, but studies in non-pregnant patients suggest CTA might be less specific in younger patients.
      • Anderson D.R.
      • Kahn S.R.
      • Rodger M.A.
      • Kovacs M.J.
      • Morris T.
      • Hirsch A.
      • et al.
      Computed tomographic pulmonary angiography vs ventilation- perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial.
      The decision to use CTA or VQ scan is also dictated by local availability and expertise. The CTA technique used to diagnose PE in nonpregnant patients should be modified as 5% to 36% of scans can be inadequate in pregnancy due to physiological changes.
      • Berrington de Gonzalez A.
      • Darby S.
      Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries.
      • U-King-Im J.M.
      • Freeman S.J.
      • Boylan T.
      • Cheow H.K.
      Quality of CT pulmonary angiography for suspected pulmonary embolus in pregnancy.
      • Ridge C.A.
      • McDermott S.
      • Freyne B.J.
      • Brennan D.J.
      • Collins C.D.
      • Skehan S.J.
      Pulmonary embolism in pregnancy: comparison of pulmonary CT angiography and lung scintigraphy.
      • Ridge C.A.
      • Mhuircheartaigh J.N.
      • Dodd J.D.
      • Skehan S.J.
      Pulmonary CT angiography protocol adapted to the hemodynamic effects of pregnancy.
      We currently advocate the use of the VQ scan as the diagnostic test in pregnancy whenever possible for the reasons listed above. However, if CTA is used, it is important to counsel patients regarding breast radiation and ensure local awareness for technique modification.
      As illustrated in Figure 2, initial testing for PE should reasonably begin with bilateral CUS. Although the likelihood of asymptomatic DVT is low, if a DVT is diagnosed in the presence of unexplained chest pain, shortness of breath or tachycardia, a PE can be assumed and ventilation-perfusion scanning avoided. If CUS is negative or if the initial bilateral leg CUS examination is not available, a ventilation- perfusion scan should be performed. If the scan is normal, no further testing is needed; if the scan is high probability, anticoagulation should be initiated. For non-diagnostic scans, either CTA or serial CUS testing, based on clinical suspicion and the presence of risk factors, should be done. If CTA is selected, a negative scan will rule out a PE while a positive scan will be diagnostic. When the CTA is inconclusive or inadequate, serial whole leg ultrasound examination or repeat testing with a VQ scan is recommended.
      • Bourjeily G.
      • Paidas M.
      • Khalil H.
      • Rosene-Montella K.
      • Rodger M.
      Pulmonary embolism in pregnancy.
      Recommendations
      • 1.
        Objective testing is required following clinical suspicion of deep vein thrombosis or pulmonary embolism. (II-2A)
      • 2.
        For the diagnosis of deep vein thrombosis, ultrasonography is recommended, and should be repeated at least once over 7 days if the initial study is negative. For each examination, the entire length of the venous system from the external iliac to the popliteal vein must be visualized and compression manoeuvres performed from the femoral to the popliteal vein. (II-2B)
      • 3.
        For the diagnosis of pulmonary embolism, either ventilation-perfusion scan or computed tomographic angiography can be used. (II-2A) In pregnant women, a ventilation-perfusion scan is the preferred test. (III-B)
      • 4.
        Neither D-dimer alone nor clinical prediction rules should be used to rule out venous thromboembolism in pregnant women without objective testing. (III-D)
      Figure thumbnail gr2
      Figure 2Algorithm for the diagnosis of pulmonary embolism in pregnant patients using the preferred VQ scan

      TREATMENT OF ACUTE VTE

      Setting

      Once an acute VTE is confirmed, therapeutic anticoagulation should be instituted promptly. There are no studies confirming the safety of outpatient management in pregnancy for women with acute VTE. Given the additional fetal concerns, pregnant women with an acute PE and/or a large proximal DVT should be considered for hospitalization or followed closely as outpatients in the initial two weeks following diagnosis if they remain hemodynamically stable.
      Recommendation
      • 5.
        Pregnant women diagnosed with acute venous thromboembolism should be hospitalized or followed closely as outpatients for the first 2 weeks after the initial diagnosis. (III-C)

      Choice of anticoagulant

      Vitamin K antagonists, such as warfarin, should not be considered for the treatment of VTE in pregnancy except in exceptional circumstances. They cross the placenta, and first trimester exposure can cause warfarin embryopathy (midfacial and limb hypoplasia, stippled bone epiphyses).
      • Ginsberg J.S.
      • Hirsch J.
      • Turner D.C.
      • Levine M.N.
      • Burrows R.
      Risks to the fetus of anticoagulant therapy during pregnancy.
      • Pauli R.M.
      • Haun J.
      Intrauterine effects of coumarin derivatives.
      They are also associated with pregnancy loss and fetal anticoagulation at the time of delivery.
      • Chan W.S.
      • Anand S.
      • Ginsberg J.S.
      Anticoagulation of pregnant women with mechanical heart valves: a systemic review of the literature.
      UH and LMWH do not cross the placenta and do not cause teratogenicity or fetal bleeding.
      • Flessa H.C.
      • Kapstrom A.B.
      • Glueck H.I.
      • Will J.J.
      Placental transport of heparin.
      • Forestier F.
      • Daffos F.
      • Capella-Pavlovsky M.
      Low molecular weight heparin (PK10169) does not cross the placenta during second trimester of pregnancy; study by direct fetal blood sampling under ultrasound.
      • Lepercq J.
      • Conard J.
      • Borel-Derlon A.
      • Darmon J.Y.
      • Boudignat O.
      • Francoual C.
      • et al.
      Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.
      • 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.
      • Greer I.A.
      • Nelson-Piercy C.
      Low-molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systemic review of safety and efficacy.
      • Ni Ainle F.N.
      • Wong A.
      • Appleby N.
      • Byrne B.
      • Regan C.
      • Tayyaba H.
      • et al.
      Efficacy and safety of once daily low molecular weight heparin (tinzaparin sodium) in high risk pregnancy.
      HIT occurs in 3% of non-pregnant patients receiving UH. It has never been reported in a pregnancy with LMWH,
      • Greer I.A.
      • Nelson-Piercy C.
      Low-molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systemic review of safety and efficacy.
      and outside of pregnancy HIT has been reported only in rare cases.
      • Linkins L.-A.
      • Dans A.L.
      • Moores L.K.
      • Bona R.
      • Davidson B.L.
      • Schulmans S.
      • et al.
      Treatment and prevention of heparin-induced thrombocytopenia.
      Due to its lower side-effect profile and ease of dosing, LMWH is recommended over UH for use in pregnant women. Table 2 outlines the pooled risk estimates of side effects associated with LMWH use in pregnancy. The specific LMWH preparation used depends on availability and costs. There is no current evidence to suggest the superiority of one preparation of LMWH over another.
      Table 1Key to evidence statements and grading of recommendations, using the ranking of the Canadian Task Force on Preventive Health Care
      Quality of evidence assessment
      The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.187
      Classification of recommendations
      Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.187
      I: Evidence obtained from at least one properly randomized controlled trialA. There is good evidence to recommend the clinical preventive action
      II-1: Evidence from well-designed controlled trials without randomizationB. There is fair evidence to recommend the clinical preventive action
      II-2: Evidence from well-designed cohort (prospective or retrospective) or case-control studies, preferably from more than one centre or research groupC. The existing evidence is conflicting and does not allow to make a recommendation for or against use of the clinical preventive action; however, other factors may influence decision-making
      II-3: Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of treatment with penicillin in the 1940s) could also be included in this categoryD. There is fair evidence to recommend against the clinical preventive action
      E. There is good evidence to recommend against the clinical preventive action
      III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committeesL. There is insufficient evidence (in quantity or quality) to make a recommendation; however, other factors may influence decision-making
      * The quality of evidence reported in these guidelines has been adapted from The Evaluation of Evidence criteria described in the Canadian Task Force on Preventive Health Care.
      • Woolf S.H.
      • Battista R.N.
      • Angerson G.M.
      • Logan A.G.
      Eel W Canadian Task Force on Preventive Health Care
      New grades for recommendations from the Canadian Task Force on Preventive Health Care.
      Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian Task Force on Preventive Health Care.
      • Woolf S.H.
      • Battista R.N.
      • Angerson G.M.
      • Logan A.G.
      Eel W Canadian Task Force on Preventive Health Care
      New grades for recommendations from the Canadian Task Force on Preventive Health Care.
      Table 2Incidence of side effects related to low molecular weight heparins in pregnancy
      Therapeutic doseProphylactic doseAny doseReferences
      Antepartum bleeding0% to 0.57%0.42%0% to 0.43%51, 171 to 173
      Postpartum bleeding1.15% to 5.6%0.92%0.94% to 1.6%51, 171 to 173
      Wound hematoma1.39%0%0.5% to 0.61%51, 171 to 173
      Major skin reaction/allergy1.15%0.96%0.5% to 1.8%51, 173
      Osteoporosis0%0.26%0.04% to 0.2%51, 173
      HIT0%0%0%51, 173
      Danaparoid and fondaparinux are heparanoid molecules that do not cross-react with HIT antibodies. Both are treatment options for pregnant women with evidence of HIT or allergic reactions to heparins.
      • Schindewolf M.
      • Mosch G.
      • Bauersachs R.M.
      • Lindhoff-Last E.
      Safe anticoagulation with danaparoid in pregnancy and lactation.
      • Mazzolai L.
      • Hohlfeld P.
      • Spertini F.
      • Hayoz D.
      • Schapira M.
      • Duchosal M.A.
      Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy.
      These agents should only be used after consultation with an appropriate specialist.
      There are currently no data on the safety in pregnancy of the oral direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban). Given their very low molecular weights, they are likely to cross the placenta and should be avoided.
      Recommendations
      • 6.
        Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for the treatment of venous thromboembolism in pregnancy. (II-2A)
      • 7.
        Heparin-induced thrombocytopenia in pregnant women is extremely rare. Consultation with a hematologist or thrombosis specialist is recommended to consider the use of heparanoids for treatment of venous thromboembolism if it occurs. (II-3B)
      • 8.
        Vitamin K antagonists should only be considered in exceptional circumstances for the treatment of venous thromboembolism in pregnancy. (II-2A)
      • 9.
        We recommend against the use of oral Xa inhibitors and oral direct thrombin inhibitors for the treatment of venous thromboembolism in pregnancy. (III-D)

      Anticoagulant dosing and monitoring

      Recommended doses for anticoagulation medications are presented in Table 3. The specific LMWH dosing is as per the manufacturer’s recommendation, based on the woman’s weight at the time of presentation.
      Table 3Dosing of anticoagulants
      Prophylactic doseIntermediate doseTherapeutic dose
      UH5000 U SC twice daily

      Obesity: 7500 U SC twice daily
      10 000 U SC twice dailyIV: 80 U/kg bolus (max 5000 U) followed by 18 U/kg and adjusted according to local nomogram
      SC: 150 to 200 U/kg twice daily
      A lower dose should be considered in women weighing less than 50 kg
      • Clark N.P.
      • Delate T.
      • Cleary S.J.
      • Witt D.M.
      Analysis of unfractionated heparin dose requirements to target therapeutic anti-Xa intensity during pregnancy.
      Target aPTT 1.5 to 2.5×baseline
      Dalteparin5000 U SC daily or twice daily >20 weeks

      Obesity: 7500 U SC daily
      100 U/kg SC daily or 5000 U SC twice daily200 U/kg daily or 100 U/kg SC twice daily
      Enoxaparin40 mg SC daily or 30 mg SC twice daily

      Obesity: 60 mg SC daily
      40 mg SC twice daily1 mg/kg SC twice daily or 1.5 mg/kg SC daily
      Nadroparin2850 U SC dailyNot applicable171 U/kg SC daily
      Tinzaparin4500 U SC daily

      Obesity: 75 U/kg daily
      4500 U SC twice daily or 9000 U SC daily175 U/kg SC daily
      Danaparoid750 U SC twice dailyNot applicable2000 U SC twice daily
      SC: subcutaneously
      There are uncertainties surrounding dosing regimens; the need for monitoring and dose increases with weight gain associated with therapeutic LMWH use in pregnancy.
      • Sarig G.
      • Brenner B.
      Monitoring of low molecular weight heparin (LMWH) in pregnancy.
      While LMWH is administered as a single daily dose for non-pregnant patients, twice a day dosing is often used in pregnancy, especially for the first month when the risk of recurrence is greatest. This practice stems from the altered renal elimination of LMWH and the impact of weight gain, both of which affect anti-Xa activity in pregnant women.
      • 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.
      • McLintock C.
      • Brighton T.
      • Chunilal S.
      • Dekker G.
      • McDonnell N.
      • McRae S.
      • et al.
      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.
      • 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.
      • Ni Ainle F.N.
      • Wong A.
      • Appleby N.
      • Byrne B.
      • Regan C.
      • Tayyaba H.
      • et al.
      Efficacy and safety of once daily low molecular weight heparin (tinzaparin sodium) in high risk pregnancy.
      • Barbour L.A.
      • Oja J.L.
      • Schultz L.K.
      A prospective trial that demonstrates that dalteparin requirements increase in pregnancy to maintain therapeutic levels of anticoagulation.
      • Norris L.A.
      • Bonnar J.
      • Smith M.P.
      • Steer P.J.
      • Savidge G.
      Low molecular weight heparin (tinzaparin) therapy for moderate risk thromboprophylaxis during pregnancy: a pharmacokinetic study.
      • Smith M.P.
      • Norris L.A.
      • Steer P.J.
      • Savidge G.F.
      • Bonnar J.
      Tinzaparin sodium for thrombosis treatment and prevention during pregnancy.
      Hence, for the treatment of acute VTE, especially major proximal VTE and PE, consideration should be given to initial monitoring of anti-Xa activity, during the first month of treatment only, to target a level of 0.6 to 1.0 U/mL 4 hours after injection, bearing in mind that target levels will vary with the LMWH used. However, the cost of the assay, the lack of correlation with clinical events, and the variability between assays makes the utility of monitoring anti-FXa activity in pregnancy controversial.
      • 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.
      If UH is selected for initial treatment, it should be administered initially as a bolus followed by a continuous infusion, using a weight-based nomogram to estimate required doses, and adjusting the infusion to keep the aPTT at 1.5 to 2.5 times baseline. After initial treatment, a switch to therapeutic subcutaneous LMWH or UH can be made. If UH is selected, it should be administered subcutaneously twice daily with doses adjusted to maintain the aPTT at 1.5 to 2.5 times pregnancy baseline at the mid-dosing interval (i.e., 6 hours after the last dose). For women with significant renal impairment (GFR<30 mL/minute) we recommend UH over LMWH.
      Recommendations
      • 10.
        For the treatment of acute venous thromboembolism in pregnancy we recommend adhering to the manufacturer’s recommended dosing for individual low molecular weight heparins based on the woman’s current weight. (II-1A) Low molecular weight heparin can be administered once or twice a day depending on the agent selected. (III-C)
      • 11.
        For pregnant women initiated on therapeutic low molecular weight heparin, baseline platelet counts should be taken and repeated a week later to screen for heparin-induced thrombocytopenia. (III-C)

      Duration of therapeutic anticoagulation

      If an acute VTE is diagnosed early in pregnancy, reducing the anticoagulation intensity after 3 months to intermediate or prophylactic (low) dose LMWH for the duration of the pregnancy is an option, although evidence confirming or disputing the safety of this option is unavailable. In the postpartum period, both LMWH and warfarin can be used.
      Recommendations
      • 12.
        For pregnant women with an acute venous thromboembolism we recommend therapeutic anticoagulation for a minimum of 3 months. (I-A)
      • 13.
        Following initial treatment, anticoagulation intensity can be decreased to intermediate or prophylactic dose for the remainder of the pregnancy and for at least 6 weeks postpartum. (III-C)

      Prevention of post-thrombotic syndrome

      Post-thrombotic syndrome is a constellation of symptoms (chronic leg swelling, discoloration, pain on walking or standing) occurring in 20% to 40% of nonpregnant patients who develop a proximal DVT.
      • Kahn S.R.
      • Ginsberg J.S.
      The post thrombotic syndrome: current knowledge, controversies, and directions for future research.
      Graded compression stockings with 30 to 40 mmHg pressure at the ankles for 2 years were previously felt to reduce this rate.
      • 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.
      A recent large placebo-controlled RCT (N=803) showed that compression stockings did not prevent post- thrombotic syndrome, nor did they influence the severity or rate of recurrence after a first proximal DVT in an older non-pregnant population.
      • Kahn S.R.
      • Shapiro S.
      • Wells P.S.
      • Rodger M.A.
      • Kovacs M.J.
      • Anderson D.R.
      • et al.
      A multicenter randomized placebo controlled trial of compression stockings to prevent the post-thrombotic syndrome after proximal deep venous thrombosis: The S.O.X. Trial.
      Observational studies are limited in pregnancy, therefore the need for prolonged use of graded compression stockings in pregnant women is uncertain and we recommend them for symptom relief alone.
      Recommendation
      • 14.
        In pregnant women with acute proximal leg deep vein thrombosis, the use of graded compression stockings can be considered for relief of symptoms. (III-C)

      Thrombolytic therapy

      Thrombolytic therapy has been used successfully in pregnant women who present with massive PE and hemodynamic instability.
      • Turrentine M.A.
      • Braema G.
      • Ramirez M.M.
      Use of thrombolytics for the treatment of thromboembolic disease during pregnancy.
      • Leonhardt G.
      • Gaul C.
      • Nietsch H.H.
      • Buerke M.
      • Schleussner E.
      Thrombolytic therapy in pregnancy.
      Streptokinase, r-tPA, and urokinase do not appear to have direct placental transfer. The risk of catastrophic bleeding with their use needs to be weighed against the risk of maternal and fetal death. The only indication for thrombolytic therapy in pregnancy is limb-threatening DVT or a massive PE.
      • Bates S.M.
      • Jaeschke R.
      • Stevens S.M.
      • Goodacre S.
      • Wells P.S.
      • Stevenson M.D.
      • et al.
      Diagnosis of DVT. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
      Recommendation
      • 15.
        Thrombolytic therapy in pregnancy should only be considered in limb-threatening deep vein thrombosis or massive pulmonary embolism. (III-C)

      Vena cava filters

      Vena cava filters are rarely required in pregnancy.
      • Decousus H.
      • Leizorovicz A.
      • Parent F.
      • Page Y.
      • Tardy B.
      • Girard P.
      • et al.
      A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du risque d’embolie pulmonaire par Interruption Cave Study Group.
      • Aburahma A.F.
      • Mullins D.A.
      Endovascular caval interruption in pregnant patients with deep vein thrombosis of the lower extremity.
      • Kawamata K.
      • Chiba Y.
      • Tanaka R.
      • Higashi M.
      • Nishigami K.
      Experience of temporary inferior vena cava filters inserted in the perinatal period to prevent pulmonary embolism in pregnant women with deep vein thrombosis.
      • Milford W.
      • Chadha Y.
      • Lust K.
      Use of a retrievable vena cava filter in term pregnancy: case report and review of the literature.
      Placement of a retrievable filter can be considered if a patient presents with an acute PE within 2 weeks of delivery or if anticoagulation therapy has to be interrupted due to major bleeding concerns. Careful planning of filter insertion with interventional radiology is necessary to minimize fetal exposure to radiation.
      Recommendation
      • 16.
        Vena cava filters should only be used in pregnant women with acute pulmonary embolism or deep vein thrombosis and contraindications to anticoagulation. (III-C)

      CEREBRAL VENOUS THROMBOSIS

      The incidence of CVT ranges from 0.01% to 0.04% in Western countries.
      • Lanska D.J.
      • Kryscio R.J.
      Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis.
      Pregnancy and the puerperium, Caesarean section, dehydration, anemia, thrombophilia, and hypertension are identified risk factors.
      • Lanska D.J.
      • Kryscio R.J.
      Risk factors for peripartum and postpartum stroke and intracranial venous thrombosis.
      • Cantu-Brito C.
      • Arauz A.
      • Aburto Y.
      • Barinagarrementeria F.
      • Ruiz-Sandoval J.L.
      • Baizabal-Carvallo J.F.
      Cerebrovascular complications during pregnancy and postpartum: clinical and prognosis observations in 240 Hispanic women.
      • Saposnik G.
      • Barinagarrementeria F.
      • Brown Jr., R.D.
      • Bushnell C.D.
      • Cucchiaron B.
      • Cushman M.
      • et al.
      Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association.
      Symptoms and signs include diffuse headache, altered consciousness, seizures, and focal neurological deficits. CT venography and/or MRI studies should be performed in suspected CVT if initial imaging modalities without contrast are negative or inconclusive.
      Once CVT is diagnosed, therapeutic dose anticoagulation should be initiated. In addition to haematologists and thrombosis specialists, other medical and surgical subspecialists may be required depending on neurological complications.
      Recommendations
      • 17.
        Computed tomographic venography and/or magnetic resonance imaging should be performed to rule out cerebral venous thrombosis if suspected. (I-C)
      • 18.
        Therapeutic dose anticoagulation should be initiated for confirmed cerebral venous thrombosis. (II-2A)
      • 19.
        Thromboprophylaxis should be considered in future pregnancies following a cerebral venous thrombosis. (II-1C)

      SUPERFICIAL THROMBOPHLEBITIS

      Superficial thrombophlebitis is inflammation with or without thrombosis of a superficial vein, isolated or associated with peripheral or central catheters. The incidence in pregnancy is 0.068%.
      • McColl M.D.
      • Ramsay J.E.
      • Tait R.C.
      • Walker I.D.
      • McCall F.
      • Conkie J.A.
      • et al.
      Superficial vein thrombosis: incidence in association with pregnancy and prevalence of thrombophilic defects.
      ST is usually self-limiting, but it can extend into the deep venous system and/or recur. Factors associated with DVT include bilateral ST, ST presenting near the deep venous system (saphenofemoral and saphenopopliteal junctions), systemic infection, absence of varicose veins, and a previous history of DVT.
      • Lutter K.S.
      • Kerr T.M.
      • Roedersheimer L.R.
      • Lohr J.M.
      • Sampson M.G.
      • Cranley J.J.
      Superficial thrombophlebitis diagnosed by duplex scanning.
      • Gorty S.
      • Patton-Adkins J.
      • DaLanno M.
      • Starr J.
      • Dean S.
      • Satiani B.
      Superficial venous thrombosis of the lower extremities: analysis of risk factors, and recurrence and role of anticoagulation.
      Concurrent PE is diagnosed in 4% of individuals with ST affecting>5 cm of a vein.
      • Wichers I.M.
      • Di Nisio M.
      • Buller H.R.
      • Middeldorp S.
      Treatment of superficial vein thrombosis to prevent deep vein thrombosis and pulmonary embolism: a systematic review.
      The preferred treatment of ST is uncertain in pregnant women. A recent trial in non-pregnant patients showed that fondaparinux (2.5 mg daily for 45 days) significantly reduced the incidence of DVT and the extension and recurrence of the ST.
      • Decousus H.
      • Prandoni P.
      • Mismetti P.
      • Bauersachs R.
      • Boda Z.
      • Brenner B.
      • et al.
      Fondaparinux for the treatment of superficial-vein thrombosis in the legs.
      A recent Cochrane meta-analysis showed that LMWH (prophylactic and therapeutic doses) and NSAIDS for 8 to 12 days were more effective than placebo in reducing the extension or recurrence of ST, but without decreasing the occurrence of symptomatic DVT.
      • Di Nisio M.
      • Wichers I.M.
      • Middeldorp S.
      Treatment for superficial thrombophlebitis of the leg.
      Since safety data on fondaparinux use is limited and extended NSAID use is discouraged in pregnancy after 26 to 28 weeks’ gestation, we recommend prophylactic or intermediate dose LMWH for 1 to 6 weeks in symptomatic women and in women with bilateral ST, ST of 5 cm or more, or ST located less than 5 cm from the deep venous system. Observation alone is recommended in women with ST who are at low risk of DVT and for those who do not require symptom control. Clinical follow-up of these women should occur within 7 to 10 days, with a repeat CUS within one week.
      Recommendations
      • 20.
        For superficial thrombophlebitis, compression ultrasound should be performed to exclude deep vein thrombosis (II-2A), and it should be repeated if proximal extension is suspected based on worsening phlebitis. (III-C)
      • 21.
        Prophylactic or intermediate dose low molecular weight heparin for 1 to 6 weeks is recommended for women with bilateral superficial thrombophlebitis, for very symptomatic women, and for superficial thrombophlebitis located<5 cm from the deep venous system (saphenofemoral and saphenopopliteal junctions) or affecting>5 cm of vein. (I-A)
      • 22.
        Observation alone is recommended in women with superficial thrombophlebitis at low risk of deep vein thrombosis and for those who do not require symptom control. Clinical follow-up of these women should occur within 7 to 10 days, with a repeat compression ultrasound within one week. (I-A)

      OVARIAN VEIN THROMBOSIS

      Ovarian vein thrombosis is an uncommon event, complicating 0.05% to 0.18% of pregnancies and affecting the right vein in up to 90% of cases.
      • Brown C.E.
      • Stettler R.W.
      • Twickler D.
      • Cunningham F.G.
      Puerperal septic pelvic thrombophlebitis: incidence and response to heparin therapy.
      • Salomon O.
      • Dulitzky M.
      • Apter S.
      New observations in postpartum ovarian vein thrombosis: experience of single center.
      Risk factors include Caesarean section, multiple gestation, and infection.
      • Salomon O.
      • Dulitzky M.
      • Apter S.
      New observations in postpartum ovarian vein thrombosis: experience of single center.
      Complications include extension of the thrombus into the vena cava and/or renal veins, and sepsis. PE occurs in 13% of cases.
      • Dunnihoo D.R.
      • Gallaspy J.W.
      • Wise R.B.
      • Otterson W.N.
      Postpartum ovarian vein thrombophlebitis: a review.
      Symptoms and signs of OVT include nausea, vomiting, guarding, constant lower abdominal or flank pain, palpable sausage-shaped tender abdominal masses, fever, rigors, and leukocytosis in the first 15 days after a delivery, abortion, or ruptured ectopic pregnancy. A pelvic ultrasound should be done initially, followed by CT and/or MRI in the case of a negative or equivocal result.
      • Twickler D.M.
      • Setiawan A.T.
      • Evans R.S.
      • Erdman W.A.
      • Stettler R.W.
      • Brown C.E.
      • et al.
      Imaging of puerperal septic thrombophlebitis: prospective comparison of MR imaging, CT, and sonography.
      Broad-spectrum parenteral antibiotics should be initiated with the diagnosis of OVT and continued for at least 48 hours after defervescence and clinical improvement.
      • Garcia J.
      • Aboujaoude R.
      • Apuzzio J.
      • Alvarez J.R.
      Septic pelvic thrombophlebitis: diagnosis and management.

      Chen KT. Septic pelvic thrombophlebitis. Available at: http://www.uptodate.com. Accessed on September 15, 2012.

      A longer treatment course is required in the presence of septicemia. Even though a small randomized study (N=14) did not report a difference in the resolution of the fever with antibiotics alone versus antibiotics plus UH,
      • Brown C.E.
      • Stettler R.W.
      • Twickler D.
      • Cunningham F.G.
      Puerperal septic pelvic thrombophlebitis: incidence and response to heparin therapy.
      concurrent anticoagulation is often recommended.
      • Salomon O.
      • Dulitzky M.
      • Apter S.
      New observations in postpartum ovarian vein thrombosis: experience of single center.
      • Garcia J.
      • Aboujaoude R.
      • Apuzzio J.
      • Alvarez J.R.
      Septic pelvic thrombophlebitis: diagnosis and management.

      Chen KT. Septic pelvic thrombophlebitis. Available at: http://www.uptodate.com. Accessed on September 15, 2012.

      • Kominiarek M.A.
      • Hibbard J.U.
      Postpartum ovarian vein thrombosis: an update.
      We recommend anticoagulation for 1 to 3 months. There are no studies to guide the risk of recurrence of OVT and the need for thromboprophylaxis in subsequent pregnancies. The risk is likely low.
      • Kominiarek M.A.
      • Hibbard J.U.
      Postpartum ovarian vein thrombosis: an update.
      Recommendations
      • 23.
        Computed tomography and/or magnetic resonance imaging (with or without angiography) are the definitive imaging modalities to rule out ovarian vein thrombosis. (II-2A)
      • 24.
        For confirmed ovarian vein thrombosis, we recommend parenteral broad-spectrum antibiotics, continued for at least 48 hours after defervescence and clinical improvement. (II-2A) Longer antibiotic therapy is necessary for septicemia or complicated infections. (III-C)
      • 25.
        For confirmed ovarian vein thrombosis, therapeutic dose anticoagulation could be considered for 1 to 3 months. (III-C)

      THROMBOPHILIA SCREENING AFTER THE DIAGNOSIS OF ACUTE VTE

      There is no consensus as to whether or not patients require thrombophilia testing following the diagnosis of an acute VTE in the non-pregnant state. The acute management of the current or subsequent pregnancies is generally not altered by knowledge of the thrombophilia status, nor is counselling regarding subsequent risks of VTE. However, patients with VTE and a known family history of PS, PC, or AT deficiency would benefit from screening, as these might affect the duration of anticoagulation required for the initial episode.
      • Ho W.K.
      • Hankey G.J.
      • Eikelboom J.W.
      Should adult patients be routinely tested for heritable thrombophilia after an episode of venous thromboembolism?.
      Screening for other inherited thrombophilias is unnecessary because the presence of these will not change management.
      • Dalen J.E.
      Should patients with venous thromboembolism be screened for thrombophilia?.
      • Middeldorp S.
      Evidence-based approach to thrombophilia testing.
      Screening for acquired thrombophilia, i.e. APLS, has been advocated for non-pregnant patients, since a persistently positive screen (over 12 weeks) could affect the duration of anticoagulation.
      • Dalen J.E.
      Should patients with venous thromboembolism be screened for thrombophilia?.
      There are concerns about applying this to pregnant women:
      • 1.
        the risk of a false positive, leading to patient anxiety, is significant,
      • 2.
        the need to prolong anticoagulation beyond the usual recommended duration for pregnant patients with APLS is uncertain, and
      • 3.
        repeat testing is required 8 to 12 weeks after delivery.
      We therefore recommend against routine screening for APLS during pregnancy, unless thrombosis occurs in an unusual site or if the results would affect the duration of anticoagulation.
      Recommendations
      • 26.
        Routine screening for all inherited thrombophilias in all women with a first episode of venous thromboembolism diagnosed in pregnancy is not indicated. (III-C)
      • 27.
        Testing for protein S, protein C, and antithrombin deficiencies is indicated following a venous thromboembolism in pregnancy if there is a family history of these particular thrombophilias, or if thrombosis occurs in an unusual site. (III-C)
      • 28.
        Testing for antiphospholipid antibodies is indicated if the results would affect the duration of anticoagulation. (III-C)

      MANAGEMENT OF ANTICOAGULATION THERAPY IN PREGNANT WOMEN WITH MECHANICAL HEART VALVES

      For management of anticoagulation therapy in these patients, we would refer clinicians to the guidelines published by American College of Chest Physicians.
      • 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.

      ANTEPARTUM THROMBOPROPHYLAXIS

      Recognizing that the pregnant state confers an increased risk for VTE is only the first step in determining which women will benefit from thromboprophylaxis during pregnancy. Although there is a 10-fold increase over baseline, the absolute risk of VTE during pregnancy remains low (0.5 per 1000 pregnancies),
      • Liu S.
      • Rouleau J.
      • Joseph K.S.
      • Sauve R.
      • Liston R.
      • Young D.
      • et al.
      Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada.
      and LMWH is not a risk-free medication (see Table 2). Hence, the difficulty in clinical practice is reconciling the low absolute risk of VTE with the low risk of side effects associated with thromboprophylaxis.
      Determining a reasonable level of absolute risk of VTE for recommending a need for thromboprophylaxis was the first step in the development of this guideline. Most experts would agree that pregnant women with an estimated absolute risk of VTE above 10% should receive thromboprophylaxis, while those with an estimated VTE risk of less than 1% might not. When the risk falls between 1% and 10% the decision to offer thromboprophylaxis would depend on the magnitude of VTE risk, the consequences of having a DVT or PE, the risks associated with thromboprophylaxis, and the patient’s and physician’s preferences.
      • Geerts W.H.
      • Bergqvist D.
      • Pineo G.F.
      • Heit J.A.
      • Samama C.M.
      • Lassen M.R.
      • et al.
      Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practive guidelines (8 th Edition).
      In this guideline we leaned towards the avoidance of VTE during pregnancy, while minimizing the number of women who would experience heparin side effects. Hence, we recommend antepartum thromboprophylaxis when the overall estimated absolute risk of VTE is greater than 1%.
      Unfortunately, the magnitude to which additional biological factors in the antepartum period increase the risk for a given patient is imprecisely reported in the literature (see Table 4). Involvement of appropriate specialists should be considered in cases of clinical uncertainty.
      Table 4Literature review of incidence of symptomatic VTE antepartum without prophylaxis according to various biological and clinical risk factors
      Incidence of symptomatic VTE
      Each dot represents one study; the superscript numerals are references to those studies.
      <1%1% to 5%>5% to 10%>10%
      Personal history of previous VTE
       Single unprovoked••91,9289
       Pregnancy-related9291
       OCP-related929190
       Single provoked (Other than OCP- or pregnancy-related)91••89,90
       FVL (hetero- and homozygosity)10089
       FVL homozygosity100
       Combined FVL and PGM heterozygosity94
       AT deficiency••176,177
      Asymptomatic thrombophilia
       FVL homozygosity••••101,178,181,182•••96,98,179
       PGM homozygosity96
       Combined FVL and PGM heterozygosity••98,182•••94,96,179
       AT deficiency••179,183••99,174••98,103••177,183
       FVL heterozygosity•••••••96–99,178–180
       PGM heterozygosity••••96,98,101,17994
       PC deficiency•••98,99,179••102,185••176,183
       PS deficiency•••103,183,185176
      Family history of symptomatic thrombophilia and unknown status
       FVL•••97,101,178
       PGM••102,184
       PC deficiency••99,103
       PS deficiency•••103,183,185
      Combined pregnancy-related risk factors
       Strict bed rest7 days+BMI25 kg/m2 at first antenatal visit109
      OCP: oral contraceptive pill
      * Each dot represents one study; the superscript numerals are references to those studies.
      Previous objectively documented VTEs which were unprovoked or related to hormonal therapy or pregnancy confer the highest risk of recurrence during pregnancy and warrant antepartum thromboprophylaxis.
      • Brill-Edwards P.
      • Ginsberg J.S.
      • Gent M.
      • Hirsh J.
      • Burrows R.
      • Kearon C.
      • et al.
      Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group.
      • Pabinger I.
      • Grafenhofer H.
      • Kaider A.
      • Kyrle P.A.
      • Quehenberger P.
      • Mannhalter C.
      • et al.
      Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis.
      • De Stefano V.
      • Martinelli I.
      • Rossi E.
      • Battaglioli T.
      • Za T.
      • Mannuucci P.M.
      • et al.
      The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis.
      • White R.H.
      • Chan W.S.
      • Zhou H.
      • Ginsberg J.S.
      Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism.
      Unprovoked or idiopathic VTEs are those occurring in the absence of clinical risk factors such as surgery, hospitalization or plaster cast immobilization within one month, and cancer.
      Thrombophilias, whether inherited or acquired, have varying propensities for VTE. High-risk thrombophilias include AT deficiency, APLS, homozygous FVL or PGM, and combined thrombophilias.
      • Meinardi J.R.
      • Middeldorp S.
      • de Kam P.J.
      • Koopman M.M.
      • van Pampus E.C.M.
      • Hamulyak K.
      • et al.
      Risk of venous thromboembolism in carriers of factor V Leiden with a concomitant inherited thrombophilic defect: a retrospective analysis.
      • Samama M.M.
      • Rached R.A.
      • Horellou M.H.
      • Aquilanti S.
      • Mathieux V.G.
      • Plu-Burean G.
      • et al.
      Pregnancy-associated venous thromboembolism (VTE) in combined heterozygous factor V Leiden (FVL) and prothrombin (FII) 20210 A mutation and in heterozygous FII single gene mutation alone.
      The more prevalent inherited thrombophilias, such as heterozygote FVL and PGM, confer a lower risk of VTE than the rarer ones, such as PS and PC deficiency.
      • Rodeghiero F.
      • Tosetto A.
      The epidemiology of inherited thrombophilia: the VITA Project. Vicenza Thrombophilia and Atherosclerosis Project.
      • Jacobsen A.F.
      • Dahm A.
      • Bergrem A.
      • Jacobsen E.M.
      • Sandset P.M.
      Risk of venous thrombosis in pregnancy among carriers of the factor V Leiden and the prothrombin gene G20210A polymorphisms.
      Since data to guide the use of thromboprophylaxis in uncommon asymptomatic thrombophilia are sparse, our recommendations for these conditions are based on estimated absolute risks for VTE in the general population
      • Middeldorp S.
      • Henkens C.M.A.
      • Koopman M.M.W.
      • van Pampus E.C.M.
      • Hamulyak K.
      • Van der Meer J.
      • et al.
      The incidence of venous thromboembolism in family members of patients with Factor V Leiden mutation and venous thrombosis.
      • Zotz R.B.
      • Gerhardt A.
      • Scharf R.E.
      Inherited thrombophilia and gestational venous thromboembolism.
      • McColl M.D.
      • Ramsay J.E.
      • Tait R.C.
      • Walker I.D.
      • McCall F.
      • Conkie J.A.
      • et al.
      Risk factors for pregnancy associated venous thromboembolism.
      rather than on data from retrospective family studies,
      • Pabinger I.
      • Nemes L.
      • Rintelen C.
      • Koder S.
      • Lechler E.
      • Loreth R.
      • et al.
      Pregnancy-associated risk for venous thromboembolism and pregnancy outcome in women homozygous for factor V Leiden.
      • Middeldorp S.
      • Libourel E.J.
      • Hamulyak K.
      • Van der Meer J.
      • Buller H.R.
      The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden.
      • Martinelli I.
      • Battaglioli T.
      • De Stefano V.
      • Tormene D.
      • Valdre L.
      • Grandone E.
      • et al.
      The risk of first venous thromboembolism during pregnancy and puerperium in double heterozygotes for factor V Leiden and prothrombin G20210A.
      • Folkeringa N.
      • Brouwer J.L.P.
      • Korteweg F.J.
      • Veeger N.J.G.M.
      • Erwich J.J.H.M.
      • Van Der Meer J.
      High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects.
      especially for PC deficiency. Note that a recent task force on APLS recommended the use of hydroxychloroquine for thromboprophylaxis in patients with both SLE and APLS,
      • Ruiz-Irastorza G.
      • Cuadrado M.
      • Ruiz-Arruza I.
      • Brey R.
      • Crowther M.
      • Derksen R.
      • et al.
      Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody- positive patients: report of a task force at the 13th International Congress on Antiphospholipid Antibodies.
      although the benefit of this recommendation has not been proven in pregnancy.
      Screening for thrombophilia in women with a previous VTE should only be done if the result will modify management in the current pregnancy, in the presence of a family history of a high-risk inherited thrombophilia, and if the woman is fully counselled about the implications of a positive result prior to testing. Screening specifically for APLS should be considered in women with a previous unprovoked VTE or VTEs in unusual sites.
      A family history of VTE alone, in the absence of a personal history or other risk factors for VTE, does not increase the personal risk of VTE sufficiently to warrant antepartum thromboprophylaxis.
      • Hron G.
      • Eichinger S.
      • Weltermann A.
      • Minar E.
      • Bialonczyk C.
      • Hirschl M.
      • et al.
      Family history for venous thromboembolism and the risk for recurrance.
      The contribution of various clinical and pregnancy- related risk factors for VTE has been derived from several population-based observational studies.
      • Lindqvist P.
      • Dahlback B.
      • Marsal K.
      Thrombotic risk during pregnancy: a population study.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study.
      • Simpson E.L.
      • Lawrenson R.A.
      • Nightingale A.L.
      • Farmer R.D.
      Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database.
      • Larsen T.B.
      • Sorensen H.T.
      • Gislum M.
      • Johnsen S.P.
      Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study.
      • Knight M.
      Antenatal pulmonary embolism: risk factors, management and outcomes.
      (Table 5)
      Table 5Literature review of incidence of symptomatic VTE antepartum without prophylaxis according to various clinical or pregnancy-related risk factors
      Incidence of symptomatic VTE
      Each dot represents one study; the superscript numerals are references to those studies.
      <0.3%0.3% to 0.5%>0.5% to<1.0%
      Maternal pre-pregnancy risk factors
       Age>35 years••••2,4,108,109
       BMI>30 kg/m2 or weight>90 kg at first antenatal visit•••••4,106,108–110107
       Weight>120 kg at first antenatal visit110
       Parity2••••2,4,106,109108
       Smoking >10 cigarettes/day or current versus never smoked•••••2,4,107–109
       Pre-existing diabetes4
       Inflammatory bowel disease4
       Varicose veins4
       Cancer4
      Risk factors related to present pregnancy
       Multiple pregnancy•••2,4,109106
       ART (singleton)••3,109109
       ART (twins)109
       Strict bedrest7 days+BMI<25 kg/m2 at first antenatal visit186109
       Preeclampsia/pre-existing hypertension••4,109
       IUGR109
       Preeclampsia+IUGR109
       Gestational diabetes••3,109
      * Each dot represents one study; the superscript numerals are references to those studies.
      However, a large case–control study of 613 232 births with 559 cases of antepartum and postpartum VTE (overall incidence of 1/1000 live births) showed that most previously identified pregnancy-related risk factors in isolation did not increase the absolute risk of antepartum VTE above 1%.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study.
      This has recently been supported by a large population- based cohort study from the UK.
      • Sultan A.A.
      • Tata L.
      • West J.
      • Fiaschi L.
      • Fleming K.
      • Nelson-Piercy C.
      • et al.
      Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom.
      For example, although maternal obesity has been identified as a risk factor, the absolute risk of VTE associated with maternal obesity alone would not warrant the use of thromboprophylaxis, even accounting for various definitions of increased BMI presented in the literature.
      • Larsen T.B.
      • Sorensen H.T.
      • Gislum M.
      • Johnsen S.P.
      Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study.
      • Robinson H.E.
      • O’Connell C.M.
      • Joseph K.S.
      • McLeod N.L.
      Maternal outcomes in pregnancies complicated by obesity.
      Notably, the combination of antenatal bedrest for7 days (defined as>90% of the time in bed) and a booking (first antenatal visit) BMI of25 kg/m2 increased the risk of antenatal VTE to approximately 6% in the large case–control study,
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study.
      warranting antepartum thromboprophylaxis with this combination of clinical factors (see Table 4). While we recognize that strict bedrest is rarely indicated in hospitalized obstetrical patients today, the significant increase in risk of VTE incurred when it is instituted cannot be overemphasized. Hence, antepartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors when the overall absolute risk of VTE is estimated to be greater than 1%, especially in patients who are in hospital, where bedrest is often prescribed.
      Due to its lower side-effect profile, LMWH is the preferred pharmacologic agent over UH for antepartum thromboprophylaxis. Table 3 presents the doses of the heparins currently available in Canada, as per the manufacturers’ recommendations. However, some women may need a dose adjustment because of their weight, and weight increases as pregnancy progresses.
      Women who are known to require antepartum thromboprophylaxis should start LMWH once the decision is made and the patient becomes pregnant. For others, ongoing evaluation of the need for antepartum thromboprophylaxis should be made throughout pregnancy, taking into account the patient’s risk factors and preferences and the side-effects associated with LMWH. Antepartum thromboprophylaxis should be continued until the onset of labour, and restarted after delivery (see relevant sections).
      Recommendations
      • 29.
        Individual risk assessment for venous thromboembolism should be performed prior to all pregnancies, once pregnancy is achieved, and repeated throughout pregnancy as new clinical situations arise. The woman’s preferences and values should be taken into account when considering the use of antepartum thromboprophylaxis. (III-B)
      • 30.
        Women at increased risk should be advised of the symptoms and signs of venous thromboembolism. (III-B)
      • 31.
        Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for antepartum thromboprophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer’s recommendation. (III-C)
      • 32.
        Routine anti-Xa and platelet level monitoring are not recommended when a patient is on a prophylactic dose of thromboprophylaxis. (II-2E)
      • 33.
        We recommend therapeutic thromboprophylaxis during pregnancy in the following situations:
        • a.
          long-term therapeutic anticoagulation used prior to pregnancy for a persistent indication; (III-B)
        • b.
          personal history of multiple previous venous thromboembolism. (III-B)
      • 34.
        We recommend intermediate or therapeutic thromboprophylaxis during pregnancy in the following situation:
        • a.
          personal history of a previous venous thromboembolism and a high-risk thrombophilia (antithrombin deficiency, antiphospholipid syndrome) not previously on anticoagulation. (III-B)
      • 35.
        We recommend prophylactic dose thromboprophylaxis during pregnancy in the following situations (absolute risk>1%):
      • a.
        personal history of a previous unprovoked venous thromboembolism; (II-2A)
      • b.
        personal history of a previous venous thromboembolism related to oral contraceptives or pregnancy; (II-2A)
      • c.
        personal history of a previous provoked venous thromboembolism and any low risk thrombophilia; (I-A)
      • d.
        asymptomatic homozygous factor V Leiden; (II-2A)
      • e.
        asymptomatic homozygous prothrombin gene mutation 20210A; (III-B)
      • f.
        asymptomatic combined thrombophilia; (III-B)
      • g.
        asymptomatic antithrombin deficiency; (III-B)
      • h.
        non-obstetrical surgery during pregnancy, with the duration of thromboprophylaxis procedure- and patient-dependent; (III-B)
      • i.
        strict antepartum bedrest for7 days in a woman with a body mass index of>25 kg/m2 at her first antenatal visit. (II-2B)
      • 36.
        Antepartum thromboprophylaxis for isolated pregnancy-related risk factors is not recommended. (III-E)
      • 37.
        Antepartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors where the overall absolute risk of venous thromboembolism is estimated to be>1%, especially in women admitted to hospital for bedrest. (II-2B)

      ASSISTED REPRODUCTIVE TECHNOLOGY

      The risk of VTE in women undergoing ART is estimated to be 0.11% per cycle of in vitro fertilization
      • Nelson S.M.
      • Greer I.A.
      Artificial reproductive technology and the risk of venous thromboembolic disease.
      ; however, in the presence of severe OHSS it is as high as 0.78%.
      • Mára M.
      • Koryntová D.
      • Rezábek K.
      • Kaprál A.
      • Drbohlav P.
      • Jirsová S.
      • et al.
      Thromboembolic complications in patients undergoing in vitro fertilization: retrospective clinical study.
      Additionally, up to 70% of VTEs in OHSS involve the upper extremity, a much higher incidence than expected.
      • Rao A.K.
      • Chitkara U.
      • Milki A.A.
      Subclavian vein thrombosis following IVF and ovarian hyperstimulation: a case report.
      • Salomon O.
      • Schiby G.
      • Heiman Z.
      • Avivi K.
      • Sigal C.
      • Levran D.
      • et al.
      Combined jugular and subclavian vein thrombosis following assisted reproductive technology—new observation.
      VTE associated with ART and OHSS may also present weeks or even months after the resolution of the OHSS.
      • Chan W.S.
      • Dixon M.E.
      The “ART” of thromboembolism: a review of assisted reproductive technology and thromboembolic complications.
      There is currently little to guide clinicians in the use of thromboprophylaxis in women undergoing ART. Extrapolating from the observational data from studies in pregnant women, we believe that in women at high risk for VTE (those identified in Table 4), instituting thromboprophylaxis at the start of ovarian stimulation, and maintaining it for the duration of the ART, would be sensible. If pregnancy is achieved, thromboprophylaxis should be continued in the antepartum period.
      For women undergoing IVF with no risk factors for VTE, routine thromboprophylaxis is unnecessary. However, for women who develop severe OHSS, thromboprophylaxis should be considered for at least 8 to 12 weeks after resolution of the OHSS. Ongoing need for thromboprophylaxis would depend on whether pregnancy is achieved in that cycle and on the presence of other antepartum risk factors (such as those in Table 5).
      Recommendations
      • 38.
        Routine thromboprophylaxis is not required for all women undergoing ovulation induction. (III-C)
      • 39.
        If severe ovarian hyperstimulation syndrome occurs with assisted reproductive technology we recommend thromboprophylaxis with low molecular weight heparin for at least 8 to 12 weeks after resolution of the syndrome. (III-B)
      • 40.
        Thromboprophylaxis with low molecular weight heparin should be considered for any women at increased risk for venous thromboembolism undergoing assisted reproductive technology at the time of ovarian stimulation. (III-B)
      • 41.
        Women who develop a venous thromboembolism in association with the use of assisted reproductive technology but who do not conceive in that cycle should be treated with therapeutic anticoagulation for a minimum of 3 months. (II-3A) Those who conceive in that assisted reproductive technology cycle should be treated as per recommendations 12 and 13 for acute venous thromboembolism in pregnancy. (I-A, III-C)

      PERIPARTUM ANTICOAGULATION AND NEURAXIAL ANAESTHESIA

      Management Before Delivery and Neuraxial Anaesthesia

      Current consensus guidelines on the use of neuraxial (epidural, spinal, combined spinal/epidural) analgesia or anaesthesia in patients on anticoagulants largely refer to the management of non-obstetric patients.
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      • Moen V.
      • Dahlgren N.
      • Irestedt L.
      Severe neurological complications after central neuraxial blockades in Sweden 1990-1999.
      • Breivik H.
      • Bang U.
      • Jalonen J.
      • Vigfusson G.
      • Alahuhta S.
      • Lagerkranser M.
      Nordic guidelines for neuraxial blocks in disturbed haemostasis from the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.
      Similar recommendations for obstetric patients are extrapolated from recommendations for non-obstetric patients and “weak” evidence (e.g. case reports, case series, pharmacokinetic studies), and do not take into account the physiological changes of pregnancy. These changes generally alter the pharmacokinetics of heparin (both LMWH and UH) in the third trimester such that a “prophylactic dose” in the third trimester may be greater than that used early in pregnancy. The recommendations in this document are taken mainly from those of the ASRA.
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      It is important to note that guidelines from other societies may differ
      • Breivik H.
      • Bang U.
      • Jalonen J.
      • Vigfusson G.
      • Alahuhta S.
      • Lagerkranser M.
      Nordic guidelines for neuraxial blocks in disturbed haemostasis from the Scandinavian Society of Anaesthesiology and Intensive Care Medicine.
      and that the recommendations regarding timing may not apply to all types of LMWH. Early consultation with an anaesthesiologist to assess risks and benefits will inform the patient of her options for intrapartum anaesthesia. Full informed consent must be obtained for neuraxial analgesia and the reasons for deciding whether or not to proceed must be documented.
      Whenever possible, women should withhold their thromboprophylaxis at the onset of labour or after their dose on the day prior to a planned induction of labour or Caesarean section. For women on therapeutic anticoagulation, a planned date and mode of delivery is recommended to help simplify their peripartum management.
      Switching from thromboprophylactic LMWH to a prophylactic dose of UH at term (37 weeks) may allow for more options with respect to labour analgesia, since neuraxial anaesthesia is contraindicated for at least 10 to 12 hours after LMWH but there is no recommended delay after a maximum dose of 10 000 units of UH per day.
      • Harnett M.J.
      • Walsh M.E.
      • McElrath T.F.
      • Tsen L.C.
      The use of central neuraxial techniques in parturients with Factor V Leiden mutation.
      Although the ASRA Guidelines suggest no delay following up to 10 000 units of UH per day, many anaesthesiologists prefer to wait a minimum of 4 hours. For women on an intermediate or therapeutic LMWH dose, the risks and benefits of discontinuing subcutaneous LMWH and changing to therapeutic subcutaneous or intravenous UH to allow for neuraxial anaesthesia once the aPTT is normal could be considered. The switch is not necessarily advantageous, however, as at these doses coagulation may be impaired for a duration similar to that with either heparin. Although not required with women on 10 000 units of UH or less, some anaesthesiologists would check an aPTT prior to neuraxial anaesthesia in all women on UH.
      Recommendations for the interval delay between the last administered dose of heparin and the insertion or removal of a neuraxial blockade or catheter are shown in Table 6. A recent platelet count should be available in the labour suite or before Caesarean section for women on anticoagulants. In the exceptional situation of a pregnant woman who has had a VTE within the past 2 to 4 weeks, peripartum use of intravenous UH during the latent stage of labour may be necessary. In these women the risk of stopping the heparin should be weighed against the benefit of a neuraxial anaesthesia, based on the anticipated duration of labour and mode of delivery. In this situation, neuraxial anaesthesia could be considered 4 hours after discontinuation of intravenous UH if the platelet count and aPTT are normal.
      Table 6Recommended timing for neuraxial procedures in relation to anticoagulation dosing in pregnant patients.
      Prophylactic doseTherapeutic dose
      Delay between last dose of anticoagulation and neuraxial anesthesia
       UHMaximum 10 000 lU/d>4 hours after stopping IV infusion, when aPTT is normal.
      No delay unless evidence of abnormal coagulation
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      When aPTT is normal after stopping subcutaneous UH, may be>12 hours.
       LMWH10 to 12 hours
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      >24 hours
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      Delay between last dose of anticoagulant and removal of neuraxial catheter
       UH4 hoursWhen aPTT Is normal
       LMWHMinimum 10 to 12 hoursMinimum 24 hours
      Delay between neuraxial anaesthesia and restarting anticoagulant
       UH1 to 8 hours
      • Butwick A.J.
      • Carvalho B.
      Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs.
      1 to 8 hours
      • Butwick A.J.
      • Carvalho B.
      Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs.
       LMWH6 to 8 hours after Initiation of neuraxial technique>24 hours if bleeding during the neuraxial block>24 hours after initiation of neuraxial technique
      >4 hours after removal of the neuraxial catheter
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      • Butwick A.J.
      • Carvalho B.
      Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs.
      >4 hours after removal of the neuraxial catheter
      • Butwick A.J.
      • Carvalho B.
      Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs.
      Although a spinal hematoma is a rare complication (estimated incidence is<1:150 000 with epidural anaesthesia and<1:220 000 with spinal anaesthetics in healthy patients
      • Vandermeulen E.P.
      • Van Aken H.
      • Vermylen J.
      Anticoagulants and spinal- epidural anesthesia.
      ), it can result in permanent neurological dysfunction.
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      • Butwick A.J.
      • Carvalho B.
      Neuraxial anesthesia in obstetric patients receiving anticoagulant and antithrombotic drugs.
      If a spinal hematoma is suspected (new onset or progressive neurological signs, back pain, or bowel/bladder dysfunction), early confirmation by MRI should be done and surgical intervention undertaken, if warranted, to achieve better outcomes.
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      • Horlocker T.T.
      What’s a nice patient like you doing with a complication like this? Diagnosis, prognosis and prevention of spinal hematoma.
      • Lee L.A.
      • Posner K.L.
      • Domino K.B.
      • Caplan R.A.
      • Cheney F.W.
      Injuries associated with regional anesthesia in the 1980s and 1990s: a closed claims analysis.
      In women on heparin, the co-existence of any factors that can increase the risk of spinal hematoma (e.g. NSAIDs, LDA in combination with heparin, thrombocytopenia, multiple neuraxial attempts, traumatic tap) should prompt a re-evaluation of the administration of neuraxial anaesthesia, independent of these guidelines. ASA alone does not appear to increase the risk of neuraxial hematomas. However epidural hematomas have been reported in the non-obstetric literature when patients have received a combination of heparin and ASA, even with an 81 mg dose.
      • Bateman B.T.
      • Mhyre J.M.
      • Ehrenfeld J.
      • Kheterpal S.
      • Abbey K.R.
      • Argalious M.
      • et al.
      The risk and outcomes of epidural hematomas after perioperative and obstetric epidural catheterization: a report from the multicenter Perioperative Outcomes Group Research Consortium.
      Neuraxial anaesthesia must be avoided in women who are fully anticoagulated or when there is evidence of altered coagulation (e.g., petechiae, bruising, altered aPTT without APLS, disseminated intravascular coagulation in patients with HELLP syndrome).
      Recommendations
      • 42.
        Women on prophylactic dose, intermediate dose, or therapeutic anticoagulation should have a discussion about options for analgesia/anaesthesia prior to delivery. (III-B)
      • 43.
        Switching from thromboprophylactic low molecular weight heparin to a prophylactic dose of unfractionated heparin at term (37 weeks) may be considered to allow for more options with respect to labour analgesia. (III-L)
      • 44.
        Discontinue prophylactic or intermediate dose low molecular weight heparin or unfractionated heparin upon the onset of spontaneous labour or the day prior to a planned induction of labour or Caesarean section. (II-3B)
      • 45.
        A recent platelet count should be available on admission in labour or before Caesarean delivery in women who have been, or are, on anticoagulants. (III-B)
      • 46.
        For women on low molecular weight heparin, neuraxial anaesthesia can be administered as a:
        • a.
          prophylactic dose: a minimum of 10 to 12 hours after the last dose; (III-B)
        • b.
          therapeutic dose: after 24 hours since the last dose. (III-B)
      • 47.
        For women on unfractionated heparin, neuraxial anaesthesia can be administered as a:
        • a.
          prophylactic dose (maximum 10 000 U/day): after no delay; (III-B)
        • b.
          therapeutic intravenous infusion: at least 4 hours after stopping the infusion and when the activated partial thromboplastin time is normal; (III-B)
        • c.
          therapeutic subcutaneous unfractionated heparin: when the activated partial thromboplastin time is normal. This may be 12 hours or longer after the last injection. (III-B)
      • 48.
        Neuraxial anaesthesia must be avoided in a woman who is fully anticoagulated or in whom there is evidence of altered coagulation. (II-3A)

      Postpartum Management of Anticoagulation After Neuraxial Anaesthesia

      After delivery, prophylactic heparin can be initiated or resumed in women who had neuraxial anesthesia once hemostasis is confirmed, there are no signs of neurological complications, and after a minimum of 4 hours following neuraxial catheter removal (see Table 6 for timing intervals). For women on intermediate or therapeutic dose LMWH, the first postpartum dose should be given no sooner than 24 hours postpartum and a minimum of 4 hours following neuraxial catheter removal. Federal Drug Administration recommendations for the timing of the first dose of LMWH following removal of a neuraxial catheter.
      US Food and Drug Administration
      The neuraxial catheter must be removed before the first LMWH dose.
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (third edition).
      For women requiring ongoing therapeutic heparin our recommendations would be (1) intravenous UH: restart, without a bolus, at a rate of 18 U/kg/hour and monitor aPTT every 6 hours, or (2) subcutaneous LMWH: restart with a low dose (5000 U) at a minimum of 4 hours after removal of the neuraxial catheter and increase to therapeutic dose LMWH after 24 hours. Assessment of the risks and benefits of anticoagulation in these patients should be ongoing within the multidisciplinary team. Intermittent pneumatic compression devices postpartum should be considered for these women at higher risk for venous thrombosis.
      Recommendations
      • 49.
        Removal of a neuraxial catheter left in situ postpartum should only be done 4, 10 to 12, or 24 hours following the administration of prophylactic dose unfractionated heparin (maximum 10 000 U/day), prophylactic low molecular weight heparin (single daily dose), or therapeutic dose low molecular weight heparin, respectively, or in the case of therapeutic unfractionated heparin, when the activated partial thromboplastin time is normal. (II-3B)
      • 50.
        Prophylactic dose low molecular weight heparin (single daily dose) may be started or restarted 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B)
      • 51.
        Therapeutic low molecular weight heparin may be started or restarted at least 24 hours after a single injection neuraxial block and a minimum of 4 hours after neuraxial catheter removal, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B)
      • 52.
        Subcutaneous unfractionated heparin may be started or restarted at least 1 hour after a single injection neuraxial block, providing there is full neurological recovery and no evidence of active bleeding or coagulopathy. (III-B)
      • 53.
        Do not administer antiplatelet agents (acetylsalicylic acid or non-steroidal anti-inflammatory drugs) concomitantly with heparin if a neuraxial catheter is left in situ postpartum. (III-D)
      • 54.
        Women on therapeutic anticoagulation who have received neuraxial anesthesia should be monitored closely for the development of a spinal hematoma. (III-B)

      POSTPARTUM THROMBOPROPHYLAXIS

      Postpartum PE is a leading cause of maternal mortality in Canada, with up to 17 maternal deaths each year.
      • Rodger M.
      Evidence base for the management of venous thromboembolism in pregnancy.
      The “per day” risk is 15- to 35-fold greater in the 6 weeks following delivery than in non-pregnant age-matched control subjects, with the highest risk being in the first 3 weeks.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study.
      • Sultan A.A.
      • West J.
      • Tata L.J.
      • Fleming K.
      • Nelson-Piercy C.
      • Grainge M.J.
      Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study.
      • Virkus R.A.
      • Lokkegaard E.C.L.
      • Bergholt T.
      • Mogensen U.
      • Langhoff-Roos J.
      • Lidegaard O.
      Venous thromboembolism in pregnant and puerperal women in Denmark 1995-2005.
      • Heit J.A.
      • Kobbervig C.E.
      • James A.H.
      • Petterson T.M.
      • Bailey K.R.
      • Melton L.J.
      Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study.
      It is generally agreed that universal postpartum thromboprophylaxis is neither cost-effective nor recommended.
      • Robertson L.
      • Wu O.
      • Langhorne P.
      • Twaddle S.
      • Clark P.
      • Lowe G.O.
      • et al.
      Thrombophilia in pregnancy: a systematic review.
      • James A.H.
      Prevention and management of venous thromboembolism in pregnancy.
      However, an institutional policy on the prevention of postpartum VTE is an Accreditation Canada required organizational practice.
      Accreditation Canada
      In weighing the risks of treatment, specifically heparin (see Table 2), versus the potential for a devastating outcome, it seems reasonable again to use an absolute VTE risk of greater than 1% in considering postpartum thromboprophylaxis (Table 7). It is important to carefully evaluate the need for thromboprophylaxis immediately after every delivery and re-evaluate it over the puerperium as additional risk factors present themselves. Women who have been on antepartum thromboprophylaxis will usually require ongoing heparin postpartum, but the reasons for continuing should be revisited. Ideally, the plan for postpartum thromboprophylaxis will have been reviewed with these women prior to delivery. Many women, however, will require thromboprophylaxis for the first time postpartum. The risk versus benefits should be continually weighed in the decision making process.
      Table 7Literature review of incidence of postpartum thromboprophylaxis recommended for single risk factors in isolation
      Incidence of symptomatic VTE
      Each dot represents one study; the superscript numerals are references to those studies.
      1% to 5%>5%
      Personal history of previous VTE
       Single••89,140
      Asymptomatic thrombophilia
       FVL homozygosity••96,181183
       APLS140
      Risk factors related to present pregnancy
       Strict antepartum bedrest7 days109
      Risk factors related to delivery and postpartum period
       >1 L postpartum hemorrhage+postpartum surgery109
       Peripartum and/or postpartum infection109
      Incidence of symptomatic VTE postpartum without prophylaxis is>1%
      * Each dot represents one study; the superscript numerals are references to those studies.
      Observational studies have demonstrated differing biological and clinical risk factors for antenatal versus postpartum VTE.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study.
      • Sultan A.A.
      • Tata L.
      • West J.
      • Fiaschi L.
      • Fleming K.
      • Nelson-Piercy C.
      • et al.
      Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom.
      • Simpson E.L.
      • Lawrenson R.A.
      • Nightingale A.L.
      • Farmer R.D.
      Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database.
      • Danilenko-Dixon D.R.
      • Heit J.A.
      • Silverstein M.D.
      • Yawn B.P.
      • Petterson T.M.
      • Lohse C.M.L.
      • et al.
      Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based case- control study.
      In the case-control study by Jacobsen et al.,
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study.
      most postpartum risk factors, aside from strict antepartum bedrest for 7 days or more, had minimal impact in isolation (Table 8, Table 9). The strongest associations were seen with combined risks. Table 8 lists the factors of sufficient risk to warrant thromboprophylaxis when 2 are present. Table 9 lists weaker associations, warranting 3 or more to raise the absolute VTE risk postpartum to>1%. Operative vaginal delivery, prolonged labour, extensive perineal trauma, or prolonged repairs have been flagged as risk factors in other guidelines.
      • Nelson-Piercy C.
      • MacCallum P.
      • Mackillop L.
      Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top guideline no. 37a.
      • McLintock C.
      • Brighton T.
      • Chunilal S.
      • Dekker G.
      • McDonnell N.
      • McRae S.
      • et al.
      Councils of the Society of Obstetric Medicine of Australia and New Zealand; Australasian Society of Thrombosis and Haemostasis. Recommendations for the prevention of pregnancy- associated venous thromboembolism.
      Evidence to support this is lacking and there are no RCTs assessing thromboprophylaxis following vaginal deliveries.
      Table 8Literature review of incidence of postpartum thromboprophylaxis recommended for any two risk factors
      Incidence of symptomatic VTE
      Each dot represents one study; the superscript numerals are references to those studies.
      <0.3%0.3% to 0.5%>0.5% to>1.0%
      Maternal pre-pregnancy risk factors
       BMI>30 kg/m2 at first antenatal visit•••106,107,109••4,140
       Smoking>10 cigarettes/day or current versus never smoked••••2,4,107,129109
       Maternal cardiac disease•••4,106,140
       SLE••4,140
       Sickle cell disease140
       Inflammatory bowel disease4
       Varicose veins4
      Risk factors related to present pregnancy
       Preeclampsia4•••2,3,109
       Preterm birth4129
       IUGR109
       Gestational diabetes109
       Placenta previa3
       Stillbirth4
      Risk factors related to delivery and postpartum period
       Emergency Caesarean section••3,109
       Any Caesarean section••••4,106,129,1402170
       >1 L postpartum haemorrhage or transfusion postpartum4109••129,140
      Combined risk factors
       Preeclampsia+IUGR109
      Incidence of symptomatic VTE postpartum without prophylaxis<1% in isolation.
      * Each dot represents one study; the superscript numerals are references to those studies.
      Table 9Literature review of incidence of postpartum thromboprophylaxis recommended for three or more risk factors
      Incidence of symptomatic VTE
      Each dot represents one study; the superscript numerals are references to those studies.
      <0.2%0.2% to 0.3%
      Maternal pre-pregnancy risk factors
       Cancer4
       Parity2••4,1092
       Age>35 years•••••2,4,5,106,109
      Risk factors related to present pregnancy
       ART109
       Multiple pregnancy••••2,4,109,140
       Placental abruption3
       PROM109
       Elective Caesarean section1093
      Incidence of symptomatic VTE postpartum without prophylaxis<1% in isolation
      * Each dot represents one study; the superscript numerals are references to those studies.
      RCTs of heparin after Caesarean section do exist with 236 women randomized over 4 trials.
      • Gibson J.L.
      • Ekevall K.
      • Walker I.
      • Greer I.A.
      Puerperal thromboprophylaxis: comparison of the anti-Xa activity of enoxaparin and unfractionated heparin.
      • Burrows R.F.
      • Gan E.T.
      • Gallus A.S.
      • Wallace E.M.
      • Burrows E.A.
      A randomized double-blind placebo controlled trial of low molecular weight heparin as prophylaxis in preventing venous thromboembolic events after caesarean section: a pilot study.
      • Ellison J.
      • Thomson A.J.
      • Conkie J.A.
      • McCall F.
      • Walker D.
      • Greer I.A.
      Thromboprophylaxis following caesarean section - a comparison of the antithrombotic properties of three low molecular weight heparins - dalteparin, enoxaparin and tinazaparin.
      • Gates S.
      • Brocklehurst P.
      • Ayers S.
      • Bowler U.
      Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low- molecular-weight heparin.
      A Cochrane systematic review concluded that there was insufficient evidence of the benefit or harm associated with thromboprophylaxis after Caesarean section due to the small numbers and different comparisons.
      • Tooher R.
      • Gates S.
      • Dowswell T.
      • Davis L.J.
      Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period.
      Overall the risk associated with any Caesarean section is modest.
      • Sultan A.A.
      • Tata L.
      • West J.
      • Fiaschi L.
      • Fleming K.
      • Nelson-Piercy C.
      • et al.
      Risk factors for first venous thromboembolism around pregnancy: a population-based cohort study from the United Kingdom.
      • Simpson E.L.
      • Lawrenson R.A.
      • Nightingale A.L.
      • Farmer R.D.
      Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Ante- and postnatal risk factors of venous thrombosis: a hospital-based case-control study.
      • Danilenko-Dixon D.R.
      • Heit J.A.
      • Silverstein M.D.
      • Yawn B.P.
      • Petterson T.M.
      • Lohse C.M.L.
      • et al.
      Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based case- control study.
      Hence, we recommend against thromboprophylaxis following a Caesarean section in the absence of at least one other risk factor in the case of an emergency, and at least two other risk factors for elective Caesarean sections.
      As the puerperium is inherently a higher risk period for VTE than the non-pregnant state, good hydration and mobilization should be encouraged for every woman postpartum.
      Recommendations
      • 55.
        Universal postpartum thromboprophylaxis is not recommended. (III-D)
      • 56.
        Assess women for increased risk of postpartum venous thromboembolism based on antepartum, intrapartum, and postpartum risk factors after every delivery and repeat as new clinical situations arise. (II-2B)
      • 57.
        Low molecular weight heparin is the preferred pharmacologic agent over unfractionated heparin for postpartum thromboprophylaxis. (III-A) Low molecular weight heparin doses should be used as per the manufacturer’s recommendation. (III-C)
      • 58.
        Pharmacologic thromboprophylaxis postpartum is recommended in the following situations:
      • Any 1 of the following risk factors (each with an absolute venous thromboembolism risk>1%):
      • a.
        history of any prior venous thromboembolism; (II-2A)
      • b.
        any high-risk thrombophilia: antiphospholipid syndrome, antithrombin deficiency, homozygous factor V Leiden or prothrombin gene mutation 20210A, combined thrombophilia; (II-2B)
      • c.
        strict bed rest prior to delivery for 7 days or more; (II-2B)
      • d.
        peripartum or postpartum blood loss of>1 litre or blood product replacement, and concurrent postpartum surgery; (II-2B)
      • e.
        peripartum/postpartum infection. (II-2B)
      • 59.
        Postpartum thromboprophylaxis should be considered in the presence of multiple clinical or pregnancy-related risk factors when the overall absolute risk is estimated to be greater than 1% drawn from the following groups:
        • a.
          any 2 of the following risk factors (each with an absolute risk of venous thromboembolism<1% in isolation):
      • i.
        body mass index>30 kg/m2 at first antepartum visit; (II-2B)
      • ii.
        smoking>10 cigarettes/day antepartum; (II-2B)
      • iii.
        preeclampsia; (II-2B)
      • iv.
        intrauterine growth restriction; (II-2B)
      • v.
        placenta previa; (II-2B)
      • vi.
        emergency Caesarean section; (II-2B)
      • vii.
        peripartum or postpartum blood loss of>1 litre or blood product replacement; (II-2B)
      • viii.
        any low risk thrombophilia: PC or PS deficiency, heterozygous factor V Leiden, or prothrombin gene mutation 20210A; (III-B)
      • ix.
        maternal cardiac disease, SLE, sickle cell disease, inflammatory bowel disease, varicose veins, gestational diabetes; (III-B)
      • x.
        preterm delivery; (III-B)
      • xi.
        stillbirth. (III-B)
        • b.
          any 3 or more of the following·risk factors (each with an absolute risk of venous thromboembolism<1% in isolation):
          • i.
            age>35 years; (II-2B)
          • ii.
            parity2; (II-2B)
          • iii.
            any assisted reproductive technology; (II-2B)
          • iv.
            multiple pregnancy; (II-2B)
          • v.
            placental abruption; (II-2B)
          • vi.
            premature rupture of the membranes; (II-2B)
          • vii.
            elective Caesarean section; (II-2B)
          • viii.
            maternal cancer. (III-B)

      Mechanical Compression Devices

      Mechanical methods of thromboprophylaxis include both graded compression stockings and intermittent pneumatic compression devices. Older evidence suggested that graded compression stockings were beneficial in reducing post-operative VTE, leading to their widespread use.
      • Sachdeva A.
      • Dalton M.
      • Amaragiri S.V.
      • Lees T.
      Elastic compression stockings for prevention of deep vein thrombosis.
      However, their benefit has recently been challenged by two large trials in stroke patients (N=5632). Thigh-high stockings did not reduce symptomatic VTE or proximal DVT,
      • Dennis M.
      • Sandercock P.A.
      • Reid J.
      • Graham C.
      • Murray G.
      • Venable G.
      • et al.
      for the CLOTS Trial Collaboration. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomized controlled trial.
      and knee-high stockings increased the risk of thrombosis.
      • Dennis M.
      • Sandercock P.A.
      • Reid J.
      • Graham C.
      • Murray G.
      • Venables G.
      • et al.
      for the CLOTS Trial Collaboration. Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial.
      In light of this new evidence we do not advocate the routine use of graded compression stockings in postpartum women to reduce the risk of VTE.
      Intermittent pneumatic compression devices have not been studied in pregnancy. Following major gynaecologic surgery associated with a high risk of VTE, they are effective if left on for 5 days or until hospital discharge, but not if removed the day after surgery.
      • Clarke-Pearson D.L.
      • Creasman W.T.
      • Coleman R.E.
      • Synan I.S.
      • Hinshaw W.M.
      Perioperative external pneumatic calf compression as thromboembolism prophylaxis in gynecologic oncology: report of a randomized controlled trial.
      In general surgery trials, they are associated with fewer major bleeding episodes than heparin but have a lower VTE risk reduction rate.
      • 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.
      Most of these RCTs were underpowered to prove efficacy in preventing PE or mortality postoperatively.
      • Clarke-Pearson D.L.
      • Abaid N.
      Prevention of venous thromboembolic events after gynecologic surgery.
      When pharmacologic treatment is not possible, such as with active bleeding, thrombocytopenia, known heparin allergy or HIT, intermittent pneumatic compression devices are a good alternative. In women at very high risk for VTE postpartum (>10%), combined mechanical and pharmacologic thromboprophylaxis is recommended.
      Recommendation
      • 60.
        Intermittent or sequential pneumatic compression devices are alternatives in women when heparin is contraindicated postpartum. When the risk of postpartum venous thromboembolism is high they may be used in combination with low molecular weight heparin or unfractionated heparin. (III-B)

      Postpartum Thromboprophylaxis: Duration of Anticoagulation

      Up to 60% of postpartum PE occurs in the 4 to 6 weeks after delivery.
      • Jacobsen A.F.
      • Skjeldestad F.E.
      • Sandset P.M.
      Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study.
      • Sultan A.A.
      • West J.
      • Tata L.J.
      • Fleming K.
      • Nelson-Piercy C.
      • Grainge M.J.
      Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study.
      • Heit J.A.
      • Kobbervig C.E.
      • James A.H.
      • Petterson T.M.
      • Bailey K.R.
      • Melton L.J.
      Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study.
      The duration of thromboprophylaxis varies with the underlying risk factors. Women with prior VTE have the highest risk and require a minimum of 6 weeks.
      • Brill-Edwards P.
      • Ginsberg J.S.
      • Gent M.
      • Hirsh J.
      • Burrows R.
      • Kearon C.
      • et al.
      Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of clot in this pregnancy study group.
      • James A.H.
      • Jamison M.G.
      • Brancazio L.R.
      • Myers E.R.
      Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality.
      Women with persistent risks that will be present throughout the puerperium (e.g. high risk thrombophilia or prolonged immobility), should also have extended thromboprophylaxis for a full 6 weeks.
      There is no evidence to guide the duration of treatment in women having only transient antepartum or intrapartum risks. Given the logistics involved in discharging women on heparin injections, individual institutions and practitioners may vary with respect to the duration of postpartum thromboprophylaxis they choose in these cases. Other guidelines recommend both options: until discharge from hospital fully mobile as a minimum
      • Schindewolf M.
      • Mosch G.
      • Bauersachs R.M.
      • Lindhoff-Last E.
      Safe anticoagulation with danaparoid in pregnancy and lactation.
      • Harnett M.J.
      • Walsh M.E.
      • McElrath T.F.
      • Tsen L.C.
      The use of central neuraxial techniques in parturients with Factor V Leiden mutation.
      or up to 1 to 2 weeks postpartum.
      • Nelson-Piercy C.
      • MacCallum P.
      • Mackillop L.
      Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. Green-top guideline no. 37a.
      • Lindqvist P.G.
      • Hellgren M.
      Obstetric thromboprophylaxis: the Swedish guidelines.
      Recommendation
      • 61.
        Women with ongoing and persistent risk factors should receive postpartum thromboprophylaxis for a minimum of 6 weeks postpartum. (II-3B)
      • 62.
        Women with transient antepartum or intrapartum risk factors should receive postpartum thromboprophylaxis until discharged from hospital or up to 2 weeks postpartum. (III-C)

      THROMBOPROPHYLAXIS TO PREVENT ADVERSE PREGNANCY OUTCOMES

      Adverse Pregnancy Conditions: Screening

      In the 1990s reports of an increase in placenta-mediated pregnancy complications (e.g. recurrent miscarriage, late fetal loss, preeclampsia, placental abruption, and intrauterine growth restriction) in women with thrombophilia appeared in the literature.
      • Dekker G.A.
      • de Vries J.I.
      • Doelitzsch P.M.
      • Huijgens P.C.
      • von Blomberg B.M.E.
      • Jakobs C.
      • et al.
      Underlying disorders associated with severe early-onset preeclampsia.
      • Rai R.S.
      • Clifford K.
      • Cohen H.
      • Regan L.
      High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies.
      • Kupferminc M.J.
      • Eldor A.
      • Steinman N.
      • Many A.
      • Bar-Am A.
      • Jaffa A.
      • et al.
      Increased frequency of genetic thrombophilia in women with complications of pregnancy.
      • Kupferminc M.J.
      • Fait G.
      • Many A.
      • Gordon D.
      • Eldor A.
      • Lessing J.B.
      Severe preeclampsia and high frequency of genetic thrombophilic mutations.
      Whereas these early studies suggested a weak association between inherited thrombophilia and placenta-mediated pregnancy complications, subsequent prospective cohort studies suggested no association between most thrombophilia and preeclampsia or SGA infants.
      • James A.H.
      Prevention and management of venous thromboembolism in pregnancy.
      • Alfirevic Z.
      • Roberts D.
      • Martlew V.
      How strong is the association between maternal thrombophilia and adverse pregnancy outcomes? A systematic review.
      • Rey E.
      • Khan S.R.
      • David M.
      • Shrier I.
      Thrombophilic disorders and fetal loss: a meta-analysis.
      • Howley H.
      • Walker M.
      • Rodger M.
      A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction.
      • Wu O.
      • Robertson L.
      • Twaddle S.
      • Lowe G.D.
      • Clark P.
      • Greaves M.
      • et al.
      Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.
      • Rodger M.A.
      • Betancourt M.T.
      • Clark P.
      • Lindqvist P.G.
      • Dizon-Townson D.
      • Said J.
      • et al.
      The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies.
      Women with APLS do have an increased risk of recurrent and late pregnancy loss.
      • James A.H.
      Prevention and management of venous thromboembolism in pregnancy.
      • Abou-Nassar K.
      • Carrier M.
      • Ramsay T.
      • Rodger M.A.
      The association between antiphospholipid antibodies and placenta mediated complications: a systematic review and meta-analysis.
      However, there is only a weak association between these complications and FVL and no association with PGM.
      • Rodger M.A.
      • Betancourt M.T.
      • Clark P.
      • Lindqvist P.G.
      • Dizon-Townson D.
      • Said J.
      • et al.
      The association of factor V leiden and prothrombin gene mutation and placenta-mediated pregnancy complications: a systematic review and meta-analysis of prospective cohort studies.
      Hence, universal thrombophilia screening in women experiencing adverse pregnancy outcomes is not indicated.
      • Wu O.
      • Robertson L.
      • Twaddle S.
      • Lowe G.D.
      • Clark P.
      • Greaves M.
      • et al.
      Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.
      What remains unknown is whether more severe placenta-mediated pregnancy complications (e.g. severe or early-onset preeclampsia, SGA<3rd percentile, major abruption) are more strongly associated with specific thrombophilia and potentially improved with antenatal thromboprophylaxis.
      Recommendations
      • 63.
        Universal screening for thrombophilias in women experiencing adverse pregnancy outcomes (severe preeclampsia, intrauterine growth restriction, stillbirth) is not indicated. (II-2D)
      • 64.
        Women with recurrent miscarriage or late pregnancy loss should be screened for antiphospholipid syndrome. (I-B)

      LMWH to Prevent Recurrent Adverse Pregnancy Conditions

      The benefit of heparin plus LDA in women with APLS and recurrent miscarriage or late fetal loss (variably defined in the different studies) is controversial.
      • Kuttah W.H.
      Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.
      • Rai R.
      • Cohen H.
      • Dave M.
      • Regan L.
      Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).
      • Farquharson R.G.
      • Quenby S.
      • Greaves M.
      Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.
      • Laskin C.A.
      • Spitzer K.A.
      • Clark C.A.
      • Crowther M.R.
      • Ginsberg J.S.
      • Hawker G.A.
      • et al.
      Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized controlled HepASA trial.
      A meta-analysis looking at 5 trials (N=334) showed that LMWH plus LDA significantly increased the live birth rate (74.3%) compared to LDA alone (55.8%) with a number needed to treat of 5.6, but with significant heterogeneity.
      • Mak A.
      • Cheung M.W.
      • Cheak A.A.
      • Ho R.C.
      Combination of heparin and aspirin is superior to aspirin alone in enhancing live birth in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression.
      This evidence modestly supports screening women with recurrent miscarriage or late pregnancy loss for APLS and using LMWH alone or with LDA to prevent recurrent miscarriage when APLS is confirmed.
      Recent RCTs, however, showed no benefit of LMWH alone or LMWH plus LDA versus no treatment or LDA alone to prevent recurrent miscarriage in women without APLS.
      • Dolitzky M.
      • Inbal A.
      • Segal Y.
      • Weiss A.
      • Brenner B.
      • Carp H.
      A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages.
      • Badawy A.M.
      • Khiary M.
      • Sherif L.S.
      • Hassan M.
      • Ragab A.
      • Abdelall I.
      Low-molecular weight heparin in patients with recurrent early miscarriages of unknown aetiology.
      • Fawzy M.
      • Shokeir T.
      • El-Tatongy M.
      • Warda O.
      • El-Refaiey A.A.
      • Mosbah A.
      Treatment options and pregnancy outcome in women with idiopathic recurrent miscarriage: a randomized placebo-controlled study.
      • Clark P.
      • Walker I.D.
      • Langhome P.
      • Crichton L.
      • Thomson A.
      • Greaves M.
      • et al.
      SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low molecular weight heparin and low-dose aspirin in women with recurrent miscarriage.
      • Kaandorp S.P.
      • Goddijn M.
      • van der Post J.A.
      • Hutten B.A.
      • Verhoeve H.R.
      • Hamulyak K.
      • et al.
      Aspirin plus heparin or aspirin alone in women with recurrent miscarriage.
      • Visser J.
      • Ulander V.-M.
      • Helmerhost F.M.
      • Lampinen K.
      • Morin-Papunen L.
      • Bloemenkamp K.W.M.
      • et al.
      Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia.
      Although there were no significant complications related to LMWH use in these trials, there were reports of injection site bruising and skin reactions highlighting the fact that heparin is not a benign treatment and should not be prescribed in the absence of evidence to support its use.
      Given that placental thrombosis is a part of the common pathophysiology of placenta-mediated pregnancy complications, it is plausible that LDA alone, heparin alone, or the combination of LDA plus LMWH might prevent recurrence of adverse pregnancy outcomes in subsequent pregnancies for women with and without thrombophilia.
      • Leduc L.
      • Dubois E.
      • Tasker L.
      • Rey E.
      • David M.
      Dalteparin and low-dose aspirin in the prevention of adverse obstetric outcomes in women with inherited thrombophilia.
      • Rey E.
      • Garneau P.
      • David M.
      • Gauthier R.
      • Leduc L.
      • Michon N.
      • et al.
      Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial.
      • Gris J.-C.
      • Chauleur C.
      • Faillie J.-L.
      • Baer G.
      • Mares P.
      • Fabbro-Peray P.
      • et al.
      Enoxaparin for the secondary prevention of placental vascular complications in women with abruption placentae (NOH-AP trial).
      • Gris J.-C.
      • Chaleur C.
      • Molinari N.
      • Mares P.
      • Fabbro-Peray P.
      • Quere I.
      • et al.
      Addition of enoxaparin to aspirin for the secondary prevention of placental vascular complications in women with severe pre-eclampsia (NOH-PE trial).
      • Kupferminc M.J.
      • Rimon E.
      • Many A.
      • Maslovitz S.
      • Lessing J.B.
      • Gamzu R.
      Low molecular weight heparin treatment during subsequent pregnancies of women with inherited thrombophilia and previous severe pregnancy complications.
      • De Vries J.I.
      • van Pampus M.G.
      • Hague W.M.
      • Bezemer P.D.
      • Joosten J.H.
      on behalf of FRUIT investigators
      Low-molecular-weight heparin added to aspirin in the prevention of recurrent early-onset pre-eclampsia in women with inheritable thrombophilia: the FRUIT-RCT.
      • Martinelli I.
      • Ruggenenti P.
      • Cetin I.
      • Pardi G.
      • Perna A.
      • Vergani P.
      • et al.
      Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.
      A review of 6 trials (N=848 women) showed that LMWH, compared to no treatment, reduced the risk of early-onset preeclampsia (RR 0.16, 95% CI 0.07 to 0.36), birth before 37 weeks (RR 0.77, 95% CI 0.62 to 0.96), and SGA infants (RR 0.42, 95% CI 0.29 to 0.59) without any significant effect on perinatal mortality.
      There was an overall reduction in a composite outcome of complications (preeclampsia, abruption, SGA infants, or fetal loss after 12 weeks) from 42.9% to 18.7% (RR 0.52, 95% CI 0.32 to 0.86).
      As we now better understand the appropriate diagnosis of DVT in pregnant women, studies elucidating diagnostic strategies for PE during pregnancy which minimize both fetal and maternal radiation exposure are still required. Even as LMWH replaces UH as the anticoagulant of choice in pregnancy, questions surrounding appropriate dosing regimens or the need for monitoring anti-Xa activity still remain.
      A 2013 Cochrane review of 9 trials (N=979) concluded that prophylactic dose heparin (UH or LMWH), compared to no treatment, decreased perinatal mortality (RR 0.40, 95% CI 0.20 to 0.78), preterm delivery<34 weeks (RR 0.46, 95% CI 0.29 to 0.73) and SGA infants (RR 0.41, 95% CI 0.27–0.61) in women at high risk.
      • Dodd J.M.
      • McLeod A.
      • Windrim R.C.
      • Kingdom J.
      Antithrombotic therapy for improving maternal or infant health outcomes in women considered at risk of placental dysfunction.
      Although this data appears promising, given that LMWH is not risk free, it should not be used routinely to reduce the risk of recurrence of all placenta-mediated complications in women, with or without thrombophilia, pending the publication of larger trials or individual patient data meta-analysis. APLS has been considered the exception in many centers, extrapolating from experience with recurrent miscarriage. However, despite the common usage of LMWH and LDA to prevent other adverse pregnancy outcomes in women with APLS, there are no published trials that support this practice.
      Recommendations
      • 65.
        Low-dose acetylsalicylic acid or low-dose acetylsalicylic acid plus low molecular weight heparin is recommended in pregnancy in women with confirmed antiphospholipid syndrome. (I-C)
      • 66.
        Low-dose acetylsalicylic acid plus low molecular weight heparin is not recommended for women with a history of recurrent miscarriage in the absence of confirmed antiphospholipid syndrome. (I-E)
      • 67.
        Low molecular weight heparin should not be used routinely to reduce the risk of recurrent placenta-mediated complications in women with or without thrombophilia (excluding antiphospholipid syndrome). (I-C)

      FUTURE DIRECTIONS

      As we now better understand the appropriate diagnosis of DVT in pregnant women, studies elucidating diagnostic strategies for PE during pregnancy which minimize both fetal and maternal radiation exposure are still required. Even as LMWH replaces UH as the anticoagulant of choice in pregnancy, questions surrounding appropriate dosing regimens or the need for monitoring anti-Xa activity still remain.
      As we unequivocally accept that VTE prevention is an important strategy to reduce maternal morbidity and mortality, we also recognize that thromboprophylaxis is not without maternal side-effects or costs. In determining the factors associated with an increased risk of VTE, in isolation or in combination, which supersede the risk of thromboprophylaxis, we extrapolated data mostly from retrospective studies. Data from further large prospective registries could yield more information on the absolute risks associated with various biologic and clinical factors, or combination of factors, which would warrant thromboprophylaxis.
      We anticipate data from further prospective studies will become available which will shed light on the effectiveness of LMWH, plus or minus LDA, in preventing recurrent adverse pregnancy outcomes in women with or without inherited thrombophilia.

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