Thromboembolism in pregnancy

Published on 09/03/2015 by admin

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Chapter 47 Thromboembolism in pregnancy

Amy Mellor

Incidence. The incidence of venous thromboembolism (VTE) is 1 in 500–2000 pregnancies.

Significance. Pregnancy is associated with a 10-fold increase in risk of VTE compared with the non-pregnant population. VTE remains a leading cause of maternal mortality in developed countries. It results in approximately 1 death per 100,000 pregnancies.

The prevalence of VTE is distributed equally between the three trimesters. Although two-thirds of events occur antenatally, the daily risk is greatest in the postnatal period. The risk of VTE after caesarean section is approximately twice that of vaginal delivery. Deep venous thrombosis (DVT) is more common in the left leg. Pelvic vein thrombosis is more common in pregnancy than in the non-pregnant population.

Predisposing factors

All three components of Virchow’s triad (venous stasis, endothelial injury and a hypercoaguable state) may be present in pregnancy.

Hypercoaguability

Pregnancy is associated with alterations in both thrombotic and fibrinolytic mechanisms. In the first trimester there is an increase in fibrinogen, prothrombin, and factors VII, VIII, IX and X. There is increased platelet aggregation and resistance to activated protein C. There is a reduction in protein S, factor XI and factor XIII. A reduction in fibrinolytic activity occurs due to a decrease in antithrombin levels and an increase in function of fibrinolytic inhibitors PAI-1 and PAI-2. After delivery there is an elevation in factors V, VII and X, and antithrombin levels return to normal.

Venous stasis

Compression of large veins by the gravid uterus and pregnancy-associated changes in venous capacitance result in a reduction in venous return from the lower limbs.

Risk factors

• previous VTE
• age >35, parity >4, obesity
• thrombophilia

• inherited: antithrombin deficiency, prothrombin gene mutation, factor V Leiden mutation, protein C deficiency, protein S deficiency
• acquired: antiphospholipid antibodies

• operative delivery, prolonged labour
• immobilisation, infection, surgery, smoking, dehydration
• nephrotic syndrome, pre-eclampsia, cardiac disease

Clinical assessment

The clinical diagnosis of VTE is insensitive and non-specific. Few women with clinically suspected VTE have the diagnosis confirmed when investigations are employed. However, when clinical suspicion exists, treatment should be instituted until the diagnosis can be excluded by objective testing.

Signs and symptoms of VTE include leg pain and swelling, lower abdominal pain, low-grade pyrexia, dyspnoea, chest pain, haemoptysis and collapse.

Diagnosis

Deep venous thrombosis (DVT)

• Doppler ultrasound is the primary study for the diagnosis of DVT.
• Lack of compressibility is 95% sensitive and >95% specific for a proximal leg vein thrombosis. It is less sensitive for calf and pelvic vein thromboses.
• Venography is considered the gold standard investigation for suspected DVT. It is rarely used due to its invasiveness and attendant ionising radiation, and because Doppler ultrasound is almost as reliable.
• Magnetic resonance imaging (MRI) may be a useful modality in the diagnosis of pelvic vein DVT, with a sensitivity approaching 100% in the non-pregnant population. No adverse effects have been documented, though the safety of MRI in pregnancy remains unproven.
• The negative predictive value of a normal D-dimer falls progressively throughout pregnancy, making it less useful at later gestations.

Pulmonary embolism

• Arterial blood gas analysis is neither sensitive nor specific for the diagnosis of pulmonary embolism (PE). A normal result is common in the presence of a PE, while respiratory alkalosis is a common feature of pregnancy.
• A chest X-ray (CXR) should be performed when PE is suspected clinically. This may identify other pulmonary pathology (e.g. pneumonia), or may reveal features associated with PE (focal opacities, atelectasis, pulmonary oedema). However, in >50% of cases of PE, the CXR will be normal.
• When the CXR is normal, Doppler ultrasound of the lower limbs should be performed. If a DVT is found, no further investigation may be required, as the treatment of the two conditions is the same. However, fewer than 30% of patients with PE have evidence of DVT at presentation.
• If both the CXR and Doppler ultrasound are normal, a computed tomography pulmonary angiogram (CTPA) or ventilation-perfusion (V/Q) scan should be performed.
• CTPA is the investigation of choice due to its higher sensitivity and specificity and lower radiation dose to the fetus compared with V/Q scanning. Due to the high dose of radiation to maternal breasts, however, CTPA does carry an increase in lifetime risk of breast cancer.

Management

• Before anticoagulant therapy is commenced, blood should be drawn for a full blood count, coagulation screen, urea and electrolytes, and liver function tests. A thrombophilia screen may be performed, but the effects of pregnancy and thrombus on the results need to be considered.
• In clinically suspected VTE, treatment with low-molecular-weight heparin (LMWH) should be given until the diagnosis is excluded by objective testing.
• In the initial management of DVT, the affected leg should be elevated and a compression stocking worn. Mobilisation should be encouraged. A temporary inferior vena caval filter may be considered in cases of iliac vein thrombosis.
• In massive PE associated with cardiovascular compromise, immediate administration of intravenous unfractionated heparin (UH) is required. A loading dose of 80 units/kg should be followed by an infusion of 18 units/kg/hour. Thrombolytic therapy or urgent thoracotomy may be considered in certain cases.

Treatment

• LMWH is the treatment of choice for confirmed VTE. Administration is via subcutaneous injection twice daily, at a dose calculated from booking weight (e.g. enoxaparin 1 mg/kg twice daily). Anti-Xa monitoring is not warranted in routine cases. Treatment with therapeutic doses should continue for the remainder of the pregnancy and for 6 weeks postpartum, due to the risk of recurrence in this period.

Labour and delivery

• Women should be advised to cease anticoagulant therapy once labour has commenced. Therapeutic LMWH should be ceased 24 hours before planned delivery. A prophylactic dose can be given the night before a planned induction of labour or caesarean section. Regional anaesthesia should not be used until 24 hours after a therapeutic dose.
• For women at high risk of recurrence of VTE around the time of delivery, intravenous UH should replace LMWH 24 hours before intervention, and cease once labour is established or 6 hours prior to caesarean section. Protamine sulfate can be given to reverse the effect of heparin if the activated partial thromboplastin time (APTT) remains elevated at the time of delivery or abnormal bleeding occurs.
• The risk of haematoma at caesarean section in anticoagulated women is increased by about 2%. For this reason, wound drains, staples or interrupted sutures should be considered.

Postpartum

• The third stage of labour should be actively managed. Prophylactic doses of anticoagulant can be given 2–6 hours after vaginal and caesarean deliveries. A dose should not be given for 4 hours after removal of an epidural catheter, and removal should be delayed until 12 hours after the last dose. Therapeutic doses of anticoagulant can be administered 24 hours after vaginal delivery and 36–48 hours after caesarean section. Warfarin can be commenced after 48 hours. Heparin should be continued until the international normalised ratio (INR) is between 2 and 3 on two consecutive days.
• A thrombophilia screen should be performed once anticoagulation therapy has been ceased and follow-up arranged.

Prophylaxis

All women should be assessed for their risk of VTE early in pregnancy or preconceptually. Anticoagulant regimens are recommended based on the degree of risk for the individual.

• Women with a history of VTE associated with a temporary risk factor and no thrombophilia should receive prophylaxis for 6 weeks postnatally. If there has been more than one episode of VTE, a single unprovoked episode, an episode of VTE in an unusual site or a family history of VTE in a first-degree relative, antenatal prophylaxis should also be recommended.
• Women with a history of VTE and a thrombophilia should receive prophylaxis antenatally and for 6 weeks postpartum. Women with antiphospholipid antibodies and a history of VTE have a 70% chance of recurrence in pregnancy.
• Women with no history of VTE and a thrombophilia are treated according to the level of risk associated with their thrombophilia. Prophylaxis throughout pregnancy and for 6 weeks postpartum is recommended in antithrombin deficiency and for homozygosity or compound heterozygosity for factor V Leiden and prothrombin gene mutations. Women with a lower risk thrombophilia may require prophylaxis in the postpartum period only.
• Women with no history of VTE or thrombophilia, but with three or more risk factors for VTE (e.g. age >35, obesity, prolonged immobility) should be considered for prophylaxis during the antenatal period and for 3–5 days postpartum.

Anticoagulant agents

Low-molecular-weight heparin (LMWH)

• LMWH is the agent of choice for prophylaxis and treatment of VTE in pregnancy.
• It is at least as effective as, and safer than, UH, with improved bioavailability and a longer half-life, and less risk of haemorrhage, heparin-induced thrombocytopenia and osteoporosis.
• Monitor by anti-factor Xa assay if required (e.g. extremes of body mass index, renal disease).
• It does not cross the placenta, and is not contraindicated in breastfeeding.

Unfractionated heparin (UH)

• UH combines with antithrombin to accelerate the inactivation of thrombin, factor Xa and other factors.
• It is the agent of choice in massive PE associated with cardiovascular collapse.
• It may be used subcutaneously for prophylaxis or treatment of VTE where LMWH is contraindicated (e.g. allergy, renal failure).
• Dosage is titrated to achieve an APTT 1.5–2.5 times the normal value, which is monitored regularly for the duration of treatment.
• Platelet count and bone mineral density should be monitored with long-term use.
• It does not cross the placenta, and is not contraindicated in breastfeeding.

Warfarin

• Warfarin interferes with the action of vitamin K on coagulation factors II, VII, IX and X, protein C and protein S, rendering them inactive.
• Warfarin crosses the placenta and has a 5% chance of teratogenesis and increased risk of miscarriage if used in the first trimester. It is associated with fetal and neonatal haemorrhage (especially intracranial), intrauterine fetal death, and maternal haemorrhage when used later in pregnancy.
• It is safe to use postpartum from 2–3 days after delivery with close INR monitoring. It is not contraindicated in breastfeeding.

Further reading

Royal College of Obstetricians and Gynaecologists 2004 Thromboprophylaxis during pregnancy, labour and after vaginal delivery. Guideline No. 37, January

Royal College of Obstetricians and Gynaecologists 2007 Thromboembolic disease in pregnancy and the puerperium: acute management. Guideline No. 28, February

Schwartz DR, Malhotra A, Weinberger S 2008 Deep vein thrombosis and pulmonary embolism in pregnancy: epidemiology, pathogenesis and diagnosis. Up To Date, August

Schwartz DR, Malhotra A, Weinberger S 2008 Deep vein thrombosis and pulmonary embolism in pregnancy: prevention. Up To Date, October

Working Group on Behalf of the Obstetric Medicine Group of Australasia. Position statement: anticoagulation in pregnancy and the puerperium. Medical Journal of Australia. 2001;175:258-263.

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