Target condition being diagnosed
Pulmonary embolism (PE) is a leading cause of maternal mortality (Chang 2003; Kobayashi 2008; Lewis 2007). In the UK, approximately 30% of the maternal deaths directly related to pregnancy were caused by thromboembolism between 2003 and 2005 (Lewis 2007). The incidence approximates 0.36 to 0.48 per 1000 pregnancies and includes the postpartum period (Heit 2005; James 2006). When PE occurs anticoagulant therapy needs to be initiated to prevent further clot formation. Anticoagulant therapy is potentially harmful as it may lead to bleeding complications and can have teratogenic effects. Therefore, an objectively confirmed diagnosis of PE is vital when commencing anticoagulant therapy.
In pregnancy, a major challenge is that many symptoms of PE are similar to physical manifestations of pregnancy, for example swollen legs, dyspnoea and tachycardia. In pregnant women with suspected PE, the diagnosis is confirmed in approximately 4% of women as compared to 30% in non-pregnant patients, making accurate diagnostic tests imperative (Ginsberg 2001).
Another issue complicating the diagnosis of PE in pregnancy is that imaging tests expose the fetus to ionizing radiation. Although the level of fetal radiation exposure is far below the threshold for inducing carcinogenic effects, physicians may be hesitant to perform imaging tests in order to conform to the 'As Low As Reasonably Achievable' principle (ALARA). Given the high index of suspicion and the dangers of misdiagnosis on the one hand encouraging diagnostic efforts, and the radiation exposure and other test complications discouraging tests on the other hand, optimal diagnostic strategies are even more crucial in pregnant women compared to non-pregnant patients.
Standard pulmonary angiography (PA) is an X-ray based imaging technique using contrast agent to visualize thrombi. It is considered the reference standard for PE but is rarely used anymore because of associated complications, high radiation doses, high costs and declining availability and expertise (Rosenberg 2007; Somarouthu 2010). In particular cases, if the presence or absence of PE remains uncertain after more common tests have been performed, such as ventilation/perfusion scintigraphy (V/Q) or computed tomography (CT), PA is still an option, including in pregnant patients.
Although the risk of pregnancy-related venous thromboembolism (VTE) is relatively high compared to non-pregnant patients, the absolute numbers of pregnant women with a clinical suspicion of PE is still low. Therefore, most physicians working in the field of thrombosis infrequently encounter pregnant women with PE and thus experience is greatly lacking.
Different tests and clinical decision rules are combined to provide the safest diagnostic strategies. Clinical decision rules are used to determine a patient’s pre-test probability of PE. With a low to moderate pre-test probability combined with a normal D-dimer test it is safe to rule out PE without using further diagnostic imaging in non-pregnant patients.
In pregnancy however, several items that form part of these rules comprise some of the normal physiologic manifestations of pregnancy, for example swollen legs or a heart rate above 100 beats/min, while other items are seldom seen in pregnancy, such as the presence of cancer. Secondly, during pregnancy D-dimer levels gradually rise. A normal D-dimer level is infrequently encountered in the second and third trimesters of pregnancy (Chabloz 2001; Quiroz 2005). Because of this rise in D-dimer levels during pregnancy and because the clinical decision rules are not validated in pregnant women, current practice does not comprise the diagnostic strategy of ruling out PE in pregnancy with a clinical decision rule with or without a D-dimer test. These tests are therefore not included in this review.
CT pulmonary angiography (CTPA) has a clinical validity comparable to PA (Quiroz 2005). It is widely available and has the potential of providing an alternative diagnosis. It is performed when a clinical decision rule and D-dimer test do not concordantly rule out PE. An intraluminal filling defect is diagnostic of a PE, while the absence of a filling defect rules out the diagnosis. An inconclusive test result is present in only a small percentage of CTPAs (20 of 2199 = 0.9% (van Belle 2006)). A still unresolved issue is the clinical relevance of isolated subsegmental emboli. The rate of isolated subsegmental emboli ranges from 4% to 18% (Nijkeuter 2008; Stein 2006). Patients with isolated subsegmental PE appear to have a more benign clinical presentation than patients with a more proximal PE, and therefore the necessity to treat these patients with anticoagulants is questionable (Le Gal 2006).
Further disadvantages of CTPA include allergic reactions to the contrast agent and contrast-related nephropathy as well as exposure of the mother and fetus to radiation. The level of fetal exposure seems acceptable provided that appropriate methods of dose reduction are applied (Nijkeuter 2006). Concerns are raised that breast tissue, which receives particularly high doses of radiation (Hurwitz 2006), is especially susceptible to its carcinogenic effects, but no evidence is available on this. The iodinated contrast agents cross the placenta and carry the potential risk of neonatal thyroid function depression, though this is not supported by recent studies (Bourjeily 2010; Webb 2005).
Perfusion scintigraphy is another well-established diagnostic modality for PE. Results of both ventilation and perfusion scanning are combined and scan results can be divided into the three categories 'PE present' (high probability), 'PE absent' (very low probability or normal) or 'inconclusive' (Sostman 2008). The sensitivity of a high probability was reported to be 77% while the specificity of a very low probability or normal scan was 98% after excluding non-diagnostic readings. These non-diagnostic readings are the V/Q scan’s main drawback; the high percentage of inconclusive test results, of around 39%, then need further testing (PIOPED 1990). Moreover, the radiation exposure to the fetus is equal to or greater than in CTPA depending on the CT scanner model and imaging protocol used and the method of estimating the exposure (Doshi 2008; Hurwitz 2006a; Winer-Muram 2002). Exposure of the mother to radiation is generally less in perfusion scanning compared to CTPA (Hurwitz 2006).
Magnetic resonance (MR) angiography has the advantage of being radiation-free. However, MR angiography is not applied in daily practice because of the long acquisition times, and studies with this technique are limited (Kanal 1992; Oudkerk 2002). Another concern is the safety of gadolinium-containing contrast agents in pregnancy (Chen 2008), although progress has been made with contrast-free MR imaging (Kluge 2004).
In practice, the clinical pathway in the case of suspicion of PE in pregnant women may differ between different physicians and also between patients. Depending on the clinical presentation, a chest X-ray or electrocardiogram can be used to rule out other diseases. Clinical decision rules and D-dimer tests are not validated for excluding PE in pregnancy, however we cannot rule out that these tests are performed in daily practice. As PE and deep vein thrombosis (DVT) are both manifestations of the same disease entity (VTE), physicians sometimes opt for compression ultrasonography (CUS) of the legs in the case of suspected PE when symptoms of DVT are also present. When the diagnosis of DVT is confirmed, no further imaging of the lungs is necessary as the treatment of PE is the same as treatment of DVT.
When no leg symptoms are present, or when DVT is excluded with ultrasonography but a clinical suspicion of PE remains, or as a first-choice diagnostic test (depending on the physician), CTPA, magnetic resonance imaging (MRI) or V/Q scanning may be applied to diagnose PE. Patients with a clinical suspicion of PE who undergo CTPA, MRI or V/Q scanning are considered the focus of this review.
As anticoagulant therapy is potentially harmful, but untreated PE can be fatal, false positive and false negative diagnostic results can have major consequences. Diagnostic tests for PE have been extensively studied in non-pregnant patients (Bounameaux 2010). Pregnant women have a five-fold increased risk of VTE compared to age-matched controls (Pomp 2008). Yet pregnant women are usually excluded from diagnostic and management studies and so a strong evidence base for the management of pregnancy-related PE is missing (Middeldorp 2011). Extrapolating results from studies in, and guidelines for, non-pregnant patients is not advisable since pregnant women form a clinically distinct subgroup for several reasons outlined below.
Physiological changes in pregnancy may mimic the symptomatology of PE, and therefore PE can more often be suspected in pregnant women. This complicates the diagnostic process since it is undesirable to unnecessarily expose patients to a diagnostic path and to radiation. On the other hand, PE is a leading cause of maternal mortality and the diagnosis should not be missed.
Clinical decision rules available for non-pregnant patients cannot be used for pregnant women because several items of these rules comprise some of the normal physiologic manifestations of pregnancy, for example swollen legs or a heart rate above 100 beats/min, while other items are seldom seen in pregnancy, such as the presence of cancer.
Another physiological change during pregnancy is the progressive rise in D-dimer levels. Without adjusting the cut-off value for the D-dimer test to detect PE the test will yield more false positive results, that is it will have a lower specificity. Raising the cut-off would theoretically decrease its sensitivity.
The main issue following in utero exposure to radiation at typical diagnostic levels is induction of malignancies. The number of excess malignancy cases up to age 15 years following irradiation in utero is considered to be 1 in 16,000 per mSv (Streffer 2003). A CTPA exposes the fetus to 0.013 mSv of radiation and a perfusion scan to 0.11 to 0.20 mSv. Given the difficulty of measuring radiation and the variations in protocols used, these numbers should be interpreted as equally low and they justify the use of radiation in order to prevent a potentially life-threatening PE. Of course radiation exposure should be kept as low as possible, in line with the ALARA principle (Hendee 1986), but at the same time clinicians need to be aware that risks of radiation need to be weighed against the risks of untreated PE or complications of unnecessary anticoagulant therapy (Nijkeuter 2004).
Finally, the average age of pregnant women is lower than the age of the participants in the studies from which diagnostic accuracy data are derived. They are therefore less likely to have cardio-respiratory comorbidity which can result in abnormal V/Q scans (Matthews 2006), though in pregnancy a raised diaphragm might result in abnormal perfusion scan results.
For these reasons, it is important to regard pregnant women as a distinct subgroup in which tests might perform differently and additional risks need to be taken into consideration. Other research groups have come to the same conclusion and from this point of view reviewed the available literature on PE diagnostics specifically for pregnant women (Bourjeily 2010a; Brown 2010; Duran-Mendicuti 2011; Nijkeuter 2006; Rodger 2010; Rosenberg 2007; Tan 2011). Although these narrative reviews are useful as guides in the clinical dilemma of suspected PE in pregnancy, they lack the rigorous and explicit methodology of a Cochrane review with its transparent guidelines, minimisation of bias and regular updates. There is a need for such a systematic review in this field where there are still many uncertainties and controversies.