Epidemiology and Pathogenesis

Venous thromboembolism (VTE), which manifests as deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major cause of maternal morbidity in developed countries,¹–³ with an estimated overall incidence of 12.1 per 10 000 and 5.4 per 10 000 pregnancies, respectively.³

The risk of VTE associated with pregnancy appears to be greater in the post-partum period when compared to the antepartum period.²–⁵ Within the antepartum period, the risk of VTE is higher in the third trimester, when compared to the first two trimesters of pregnancy.^4,5 The post-partum period, which is associated with an increased risk of VTE, extends up to six weeks post-delivery²–⁵; recent studies suggest that this period of risk extends up to six months post-partum in patients with specific co-morbidities.⁶

In recent years, there is increased recognition that the use of fertility treatments is associated with the development of VTEs located in the upper extremities. An awareness of this complication, which often presents in the first trimester following fertility treatment, is important for prompt diagnosis and treatment.⁷–¹⁰

D-dimer Testing

As D-dimer increases during pregnancy, testing was deemed to have limited utility in pregnant patients in ruling out the presence of DVT or PE. However, D-dimer testing may still have a role in assisting with the diagnosis of VTE in pregnant patients if higher cut-points specific for pregnant patients are established.¹⁵ Several recent studies have addressed D-dimer in pregnancy.^16–18 Results were variable but low D-dimer results might be useful to avoid imaging in pregnant women who are considered at low risk for PE, especially in the first trimester. However, a negative D-dimer cannot safely rule out PE when the clinicians’ assessment is that PE is the most likely diagnosis.

Diagnostic Imaging of DVT and PE during pregnancy

Currently, diagnostic imaging is central to the exclusion of VTE when pregnant patients present with suspected DVT or PE. While there are few safety concerns with ultrasonography when it is used to exclude DVT, there were previous concerns regarding the sensitivity of the test in identifying isolated iliac DVT when it presents in pregnancy.

With respect to the diagnosis of PE during pregnancy, either ventilation-perfusion (VQ) scanning or computed tomography pulmonary angiography (CTPA) can be considered. The choice of either test depends on consideration of several factors discussed below.

Common approaches described in several guidelines used for the diagnosis of DVT and PE are described in the following sections.^9,10

Diagnosis of DVT in Pregnancy

DVT is suspected when a patient complains of unilateral groin or leg pain (calf or thigh), with or without associated swelling or redness. Most (88%) lower-extremity DVTs during pregnancy present in the left leg.¹⁹

Lower extremity DVTs during pregnancy likely originate in the proximal veins, i.e. iliac and femoral vein, and propagate distally,¹¹ unlike for the general non-pregnant population.²⁰ The ability of ultrasonography (which includes both compression manoeuvres from the femoral vein to the popliteal, and direct imaging of the iliac vein) to diagnose DVTs in the lower extremities was investigated in at least two prospective studies.^21,22 Both these studies demonstrated that compression manoeuvres performed along the entire proximal venous system from the femoral to the popliteal, with direct imaging of the external iliac vein to ensure normal flow would exclude most DVTs in pregnant women presenting with suspicious symptoms. If this test was repeated over seven days, the incidence of venous thromboembolism during follow-up was 0.49% (95% confidence interval [CI] 0.09%–2.71%). ²²

The diagnostic approach to DVT is shown in Figure 10.1.

Figure 10.1 Diagnosis of deep venous thrombosis (DVT) in pregnancy.

When a pregnant patient presents with suspicious symptoms, compression ultrasound (CUS) should be performed along the entire proximal venous system of the symptomatic leg with direct visualization of the iliac vein. If DVT is diagnosed definitively by compression manoeuvres along the length of the femoral to popliteal vein, treatment should be initiated. If isolated iliac DVT is suspected using direct imaging of the iliac vein and/or abnormal flow is detected in the iliac vein, two approaches can be considered: (a) imaging with magnetic resonance imaging (MRI), (b) re-imaging of the symptomatic leg with US over several days (to demonstrate progression) while initiating anticoagulation.

Diagnosis of PE in Pregnancy (Figure 10.2)

Pregnant patients complaining of pleuritic chest pain and shortness of breath, with risk factors for VTE, will require diagnostic imaging to exclude PE if other pregnancy-associated conditions cannot be excluded on history. These common conditions include gastro-oesophageal reflux, physiological dyspnoea of pregnancy and musculoskeletal pain associated with the gravid uterus.

Pregnant women with suspicious symptoms of PE who warrant investigation would require the use of either VQ scanning or CTPA to exclude PE.^9,10 See also Chapter 20, Radiological Imaging of the Chest in Pregnancy.

There are no published studies comparing the sensitivity and specificity of CTPA and VQ scanning in the diagnosis of PE in pregnancy.²³ The decision to use either test is usually dictated by local availability and expertize. When counselling patients about the choice of tests, several issues should be discussed:

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   1. Consideration of radiation risks to the fetus at various trimesters of exposure²⁴ and to maternal breast tissue²⁵

   
   
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   2. Suspicion of an alternate diagnosis for which CTPA may be indicated

   
   
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   3. Safety of contrast agent required for CTPA²⁶

   
   
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   4. The potential for non-diagnostic studies²³ or ‘inadequate’ studies associated with both CTPA and VQ scanning^27,28 and the need for further testing

   
   
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   5. Uncertain accuracy of either tests in the absence of studies utilizing a reference standard.²³

The approach to PE diagnosis during pregnancy has been detailed in several guidelines^9,10 and are summarized in Figure 10.2A (VQ scan) and B (CT Scan).

Figure 10.2 (a) Diagnosis of pulmonary embolism (PE) in pregnancy. (b) Diagnosis of pulmonary embolism using computed tomography pulmonary angiography (CTPA).

For both diagnostic modalities, initial testing with bilateral whole leg US would eliminate the need for unnecessary radiation exposure with further testing if DVT is diagnosed.^9,10 The likelihood of diagnosing a DVT in this setting is, nevertheless, low.

If a pregnant woman with suspected PE undergoes VQ scanning and is found to have a normal scan, PE is excluded. If she has a high probability scan, PE is diagnosed (Figure 10.2A). However, if she has a non-diagnostic scan, testing with CTPA should be considered. Similarly, for a patient who undergoes CTPA and is subsequently found to have an inadequate study (Figure 10.2B), further testing with a VQ scan would be advised.

The risk of misdiagnosis, and the need to achieve greater certainty about the presence or absence of PE during pregnancy is important because of the long-term implications for the patient (e.g. the need for thromboprophylaxis in future pregnancies or the safety of subsequent oral contraception).

Low Molecular Weight Heparin (LMWH)

The anticoagulant of choice during pregnancy is low molecular weight heparin (LMWH).⁸–¹⁰

LMWH is safe for the fetus, and is associated with a low risk of adverse effects during pregnancy.³² In a systematic review of 64 studies involving 2777 pregnancies, where the majority of patients were on low-doses of LMWH, the rate of significant bleeding was 12 of 2777 (0.43%; 95% CI, 0.22–0.75%) for antenatal bleeding, 26 of 2777 (0.94%; 95% CI, 0.61–1.37%) for post-partum haemorrhage and 17 of 2777 (0.61%, 95% CI, 0.36–0.98%) for wound haematoma. Other reported complications from the review included allergic skin reactions in 1.80% (95% CI, 1.34–2.37%) and osteoporotic fracture in 0.04% (95% CI, < 0.01–0.20%) of pregnancies, with no cases of heparin-induced thrombocytopenia reported. The low risk of global complications from this review is reassuring.

The selection of LMWH preparation for use during pregnancy is based largely on local availability [Table 10.1].

Dosing of LMWH for the purpose of treating acute VTE is based on patient’s weight as per manufacturers’ recommendations.⁸–¹⁰ For pregnancy, this weight could either be pre-pregnant or current weight.⁸–¹⁰ In practice, the weight used corresponds to a pregnancy weight obtained in early trimesters.¹⁰ If a patient has excessive weight gain (>25 kg) during pregnancy, one could consider increasing the dose of LMWH administered. Therapeutic LMWH is administered once daily or in two divided doses (Table 10.1). In the absence of clinical trials in pregnant patients, and extrapolating from studies in non-pregnant patients,⁸–¹⁰ acute VTE during pregnancy should be treated for a minimum of three months. Pregnant women with acute DVT are usually treated with LMWH for the duration of pregnancy, and at least six weeks post-partum. If a patient was diagnosed with an acute VTE in the first trimester of pregnancy, a dose reduction to intermediate or low-dose LMWH could be considered after three months of therapy in specific cases to allow patients access to delivery choices and analgesic options at term.

The need to monitor LMWH treatment for acute VTE with anti-Xa levels during pregnancy is uncertain. One could consider monitoring anti-Xa levels in pregnant patients on therapeutic doses if reduced renal function is also present or if obstetrical bleeding is ongoing.⁸–¹⁰

Unfractionated Heparin

Unfractionated heparin (UH) currently has a limited role for the ongoing treatment of VTE during pregnancy as it is now largely replaced by LMWH. UH is still considered for ‘bridging’ in high-risk situations around labour and delivery in patients with recent extensive VTE (<2–4 weeks) at delivery, during which any interruption of anticoagulation with LMWH is perceived to be risky for VTE recurrence.⁸

Thrombolytic Therapy

Thrombolytic therapy is indicated during pregnancy in patients who present with massive PE and haemodynamic instability, or limb-threatening DVT.⁸–¹⁰ Recombinant tissue plasminogen activator (rt-PA) does not appear to have direct placental transfer and has been safely used during pregnancy.³³ Use of rt-PA within 48 hours of delivery may be associated with massive bleeding, especially for patients who have had caesarian section (CS); post-partum patients in these situations would require activation of a massive transfusion protocol and surgical expertise if thrombolytic therapy is even to be considered.³⁴

Caval Filter

Vena cava filters are rarely required during pregnancy for proximal DVT,³⁵ unless there is major contraindication to anticoagulation.⁸–¹⁰ The insertion of a caval filter during pregnancy would require some consideration of imaging modality and associated radiation exposure risk safest for the developing fetus.