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Deep Vein Thrombosis and Pulmonary Embolus in Pregnancy

- Virchow triad - Vascular injury: vessel injury during delivery - Venous stasis: ↓ venous flow in legs from 25-29 weeks until 6 weeks postpartum, ↓ mobility - Hypercoagulability: ↑ coagulation factors (fibrin, factors II/VII/VIII/XI/X, von Willebrand factor [vWF]), ↓ fibrinolytic activity, and free protein S

- PE - Ventilation-perfusion lung scan (V/Q scan) - Positive: subsegmental perfusion defect - Preferred in stable patient - ↑ risk of childhood cancer, ↓ risk of maternal breast cancer compared to computed pulmonary angiogram(CTPA)

- Pregnant women on treatment anticoagulation prior to pregnancy: transition to LMWH at adjusted dose or 75% of therapeutic dose (2)[C] - No need for monitoring (unless at the extremes of weight guidelines or renal dysfunction-follow antifactor Xa 4-6 hours postinjection = 0.6-1.0 U/mL) - ↓ risk of bleeding, heparin-induced thrombocytopenia (HIT), and heparin-induced osteoporotic fractures - Other potential side effects: cutaneous allergic reactions, bruising/pain

- Thrombolytic therapy - Limited experience; life-saving in event of massive PE or hemodynamic compromise - No reports of placental abruption - Contraindicated within 10 days of cesarean or delivery but reported success within 1 hour of vaginal delivery and 12 hours of cesarean

- Admit for - Pulmonary embolus - Hemodynamic instability - Large clots - Maternal comorbidities

para>4-5 — greater risk than in nonpregnant population

Etiology and Pathophysiology

  • Virchow triadVascular injury: vessel injury during deliveryVenous stasis: ↓ venous flow in legs from 25-29 weeks until 6 weeks postpartum, ↓ mobilityHypercoagulability: ↑ coagulation factors (fibrin, factors II/VII/VIII/XI/X, von Willebrand factor [vWF]), ↓ fibrinolytic activity, and free protein S

Risk Factors

  • History of VTE (15-25% are recurrent cases)
  • Inherited or acquired thrombophiliasHigh risk: antithrombin deficiency, double heterozygous or homozygous factor V Leiden, or prothrombin G20210ALow risk: heterozygous factor V Leiden, prothrombin G20210A, protein C or S deficiency
  • Antiphospholipid syndrome
  • Age >35 years old
  • Obesity
  • Black race
  • Heart disease
  • Sickle cell disease
  • Diabetes
  • Lupus
  • Smoking
  • Multiple pregnancies (parity, gestation)
  • Operative delivery

Alert

Risk of VTE is higher in the postpartum phase; incidence of PE is 2.5-20 times higher after cesarean.

General Prevention

  • Screening for thrombophilias even after diagnosis during pregnancy is of limited value.
  • Early mobilization, graduated compression stockings for low-risk groups
  • Antepartum thromboprophylaxis for high-risk thrombophilia with family history of VTE, ≥2 prior VTE (unprovoked, pregnancy- or estrogen-related) (2)[C]. If no family history, suggest postpartum prophylaxis for 6 weeks only with prophylactic or intermediate dose low-molecular-weight heparin (LMWH) (2)[B].
  • Anticoagulation may not be required if prior VTE was not pregnancy-related and associated with a risk factor no longer present.
  • Consider thromboprophylaxis for past single episode of idiopathic VTE, low-risk thrombophilia with past VTE, morbid obesity (BMI >40), bedridden patients, and assisted reproduction technologies.

Diagnosis

Alert

Many classic signs and symptoms of VTE can mimic conditions of normal pregnancy.

History

  • Often asymptomatic
  • DVT: leg pain, tenderness, swelling (most common in left leg [70-90%] due to right iliac artery overlying left iliac vein)
  • Iliac vein thrombosis: abdominal/back pain, entire leg swelling
  • PE: dyspnea, pleuritic pain, cough

Physical Exam

  • DVT: asymmetric limb swelling (>2-cm discrepancy as compared with opposite side), Homans sign
  • PE: tachycardia, tachypnea

Differential Diagnosis

  • Symptoms of normal pregnancy
  • DVT: cellulitis, musculoskeletal pain, superficial venous thrombosis, compartment syndrome
  • PE: myocardial infarction (MI), pneumonia, aortic dissection

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

  • D-dimer: normally ↑ with pregnancy
  • Complete blood count: for baseline platelet
  • Chest x-ray to rule out alternative diagnoses
  • DVT
  • Compressive duplex ultrasound (US) (1)[A]Sensitivity = 97%, specificity = 94%↓ accuracy in isolated calf or iliac thrombosis

Follow-up tests & special considerations

  • Magnetic resonance direct thrombus imaging (MRDTI)If US is negative or equivocal and iliac vein thrombosis suspectedIf unavailable, pulsed Doppler study and computed tomography (CT)
  • PEVentilation-perfusion lung scan (V/Q scan)Positive: subsegmental perfusion defectPreferred in stable patient↑ risk of childhood cancer, ↓ risk of maternal breast cancer compared to computed pulmonary angiogram(CTPA)
  • CTPAPositive: intraluminal filling defect in segmental or greater vessel in same distribution as perfusion defect on V/Q scanUse when V/Q scan is indeterminate or in unstable patient.Breast shields ↓ radiation exposure
  • If CT is performed before V/Q: positive if subsegmental filling defect on CT corresponds to perfusion defect on V/Q

Treatment

General Measures

  • Anticoagulant confirmed acute VTE (DVT, PE)
  • LMWH and unfractionated heparin (UFH) do not cross the placenta and are the first-line drug of choice.
  • Warfarin crosses the placenta (teratogenic).1st trimester exposure (6-12 weeks): midface hypoplasia, stippled chondral calcification, scoliosis, short proximal limbs/phalanges2nd and 3rd trimester exposure: fetal intracranial hemorrhage, schizencephaly

Medication

First Line

  • LMWH (1)[B],(2): split dosing (↑ renal excretion causing ↓ half-life), weight-based
  • Treatment doses (3):Enoxaparin<50 kg: 40 mg b.i.d.; 50-69 kg: 60 mg b.i.d.; 70-90 kg: 80 mg b.i.d.; >90 kg: 100 mg b.i.d.Dalteparin (Fragmin)<50 kg: 5,000 U b.i.d.; 50-69 kg: 6,000 U b.i.d.; 70-90 kg: 8,000 U b.i.d.; >90 kg: 10,000 U b.i.d.Tinzaparin:175 U/kg daily
  • Prophylactic doses (3):Enoxaparin (Lovenox)<50 kg: 20 mg daily; 50-90 kg: 40 mg daily>90 kg: 40 mg b.i.d.; very high risk: 0.5-1.0 mg/kg b.i.d.Dalteparin<50 kg: 2,500 U daily; 50-90 kg: 5,000 U daily; >90 kg: 5,000 U b.i.d.; very high risk: 50-100 U/kg b.i.d.Tinzaparin<50 kg: 3,500 U daily; 50-90 kg: 4,500 U daily; >90 kg or very high risk: 4,500 U bidPregnant women on treatment anticoagulation prior to pregnancy: transition to LMWH at adjusted dose or 75% of therapeutic dose (2)[C]No need for monitoring (unless at the extremes of weight guidelines or renal dysfunction-follow antifactor Xa 4-6 hours postinjection = 0.6-1.0 U/mL)↓ risk of bleeding, heparin-induced thrombocytopenia (HIT), and heparin-induced osteoporotic fracturesOther potential side effects: cutaneous allergic reactions, bruising/pain

Second Line

  • UFH if LMWH is unavailable-monitor activated partial thromboplastin time (aPTT) 6 hours postinjection = 1.5-2.5Consider switching from LMWH to UFH in the last few weeks of pregnancy, follow aPTT (limited evidence of benefit although easily reversible).
  • PE late in pregnancyIV heparin: Stop once active labor begins or cesarean is considered.Reverse with protamine.

Alert

Generally, advise expectant mothers to stop LMWH once in labor.

Issues for Referral

  • Anticoagulation monitoring clinic
  • High-risk obstetrical care for continued care
  • If PE is diagnosed late in pregnancy: Transfer to medical center with maternal-fetal, neonatal, and cardiothoracic units as well as interventional radiology and vascular surgery.

Additional Therapies

  • Supplemental oxygen to maintain O2 >95%
  • Retrievable inferior vena cava (IVC) filterIn patients with anticoagulation contraindications or in whom extensive VTE develops within 2 weeks of delivery
  • Thrombolytic therapyLimited experience; life-saving in event of massive PE or hemodynamic compromiseNo reports of placental abruptionContraindicated within 10 days of cesarean or delivery but reported success within 1 hour of vaginal delivery and 12 hours of cesarean

Surgery/Other Procedures

  • Spinal anesthesia may be done whenSQ LMWH: 10-12 hours after last prophylactic dose or 24 hours after last therapeutic dose (1)[C]SQ UFH: 24 hours after the last doseIV UFH: 6 hours after stopped
  • For induction or planned cesareanDay prior: Stop LMWH or give 50% of dose.Day prior or 2 days prior: Switch to UFH.

Complementary & Alternative Therapies

  • Bed restNot recommended unless phlegmasia occurs
  • Compression stockings (30-40 mm Hg)↓ risk of postthrombotic syndrome by 50% on affected leg up to 2 years after diagnosis
  • Pneumatic compression devicesIf anticoagulation is temporarily discontinued or undergoing cesarean

Inpatient Considerations

Admission Criteria/Initial Stabilization

  • Admit forPulmonary embolusHemodynamic instabilityLarge clotsMaternal comorbidities

Discharge Criteria

  • Therapeutic dose achieved or definitive treatment completed
  • Hemodynamically stable
  • Reliable follow-up/access to care available

Ongoing Care

Follow-up Recommendations

  • Postpartum anticoagulation for acute VTE: LMWH or UFH: resume 4-6 hours after vaginal delivery, 6-12 hours after cesarean (1)[B], 12 hours after removal of epidural catheter, 24 hours after neuraxial anesthesiaContinue anticoagulation for at least 6 weeks postpartum, generally for total of at least 3-6 months (2)[C]
  • After cesareanPharmacologic thromboprophylaxis or mechanical prophylaxis if anticoagulation contraindicated (2)[B]Prophylactic LMWH with mechanical prophylaxis if at high risk

Patient Monitoring

If acute VTE is diagnosed, consider screening for inherited thrombophilias postpartum after anticoagulation treatment is complete.

Patient Education

  • Hormonal contraceptives↑ VTE with inherited thrombophilias; consider progestin-only methods
  • Breastfeeding warfarin, LMWH, and UFH are safe during breastfeeding (1)[B].

Prognosis

  • 20% of untreated proximal (above knee) DVTs progress to PEs; 10-20% of PEs are fatal; risk is decreased 5-10-fold with anticoagulation therapy.
  • Recurrence rate: 1.4-11.1%

Complications

  • Fatal PE
  • Arterial embolization if AV communication is present (e.g., patent foramen ovale)
  • Chronic venous insufficiency
  • Postthrombotic syndrome
  • Bleeding with anticoagulation
  • Phlegmasia cerulea dolens

References

1.James A. Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol. 2011;118(3):718-729.

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2.Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2)(Suppl):e691S-e736S.

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3.Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med. 2008;359(19):2025-2033.

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Additional Reading

  • Bourjeily G, Paidas M, Khalil H, et al. Pulmonary embolism in pregnancy. Lancet 2010;375(9713):500-512. []
  • James AH, Jamison MG, Brancazio LR, et al. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006;194(5):1311-1315. []
  • Picklesimer AH, Clarke-Pearson D. Deep vein thrombosis and pulmonary embolism. In: Adams Hillard P, ed. 5-Minute Clinical Consult: Obstetrics & Gynecology. Philadelphia, PA: Lippincott Williams & Wilkins; 2008:374-375.

Codes

ICD09

  • 671.30 Deep phlebothrombosis, antepartum, unspecified as to episode of care or not applicable
  • 673.20 Obstetrical blood-clot embolism, unspecified as to episode of care or not applicable

ICD10

  • O22.30 Deep phlebothrombosis in pregnancy, unspecified trimester
  • O88.219 Thromboembolism in pregnancy, unspecified trimester

SNOMED

  • 682004 Thrombosis complicating pregnancy AND/OR puerperium (disorder)
  • 200284000 Obstetric pulmonary embolism

Clinical Pearls

  • PE is the leading cause of maternal death in the developed world with 4-5 times increased risk of VTE compared to nonpregnant population.
  • Highest risk of VTE is in the postpartum period.
  • LMWH is the first-line drug for acute VTE treatment and thromboprophylaxis.
  • Continue treatment at least 6 weeks postpartum.