Diagnosis of Pulmonary Embolism During Pregnancy

Pulmonary embolism (PE) is among the most common causes of maternal death in developed countries (1, 2). A potential explanation, besides the fact that pregnancy is associated with an increased risk for venous thromboembolism (VTE), is that diagnosing PE is particularly challenging during pregnancy. Pregnant women often have symptoms and signs suggestive of PE, such as shortness of breath or tachycardia (3). Evidence to guide clinicians on how to manage women with suspected PE is limited (4, 5). Because no prospective diagnostic management study has been published, clinical practice guidelines provide highly variable recommendations (59). Use of conventional diagnostic algorithms for PE is limited by several factors. Pregnant women were excluded from studies that derived and validated models assessing pretest clinical probability of PE, and no specific tool to assess pretest probability is available in this setting (7, 10). In the nonpregnant population, the D-dimer test, a simple, noninvasive, and inexpensive blood test, may be used to rule out PE in around 30% of outpatients who do not have a high pretest clinical probability (1114). The lack of a pretest probability assessment tool and the lack of prospective data confirming the safety of ruling out PE on the basis of a negative D-dimer result have limited the adoption of the D-dimer test in this setting. Moreover, D-dimer levels increase during pregnancy, limiting the chance of a negative result, although the exact yield of D-dimer for the diagnosis of VTE during pregnancy has never been formally evaluated (15). Given the limitations of noninvasive testing, most pregnant women with suspected PE require chest imaging tests, either a ventilationperfusion (V/Q) lung scan or computed tomography pulmonary angiography (CTPA). Which to use during pregnancy has been a matter of debate, mainly due to concerns about the consequences of radiation for the mother and the fetus (16, 17). However, scientific societies and experts agree that the risks associated with either test are much lower than the potential risks of inappropriate or incomplete diagnostic management, such as death due to undiagnosed PE or bleeding and long-term management consequences of misdiagnosed PE (9, 1820). The rate of inconclusive test results leading to further testing is also a concern, with some retrospective studies suggesting that the rate of inconclusive CTPA results is much higher during pregnancy (21, 22). Use of bilateral lower limb venous compression ultrasonography (CUS) before chest imaging has been advocated. The finding of proximal deep venous thrombosis (DVT) is highly suggestive of PE, allowing for confirmation of the diagnosis without the need for additional chest imaging or anticoagulant treatment (23). However, others have raised concerns over the limited yield of CUS in the absence of DVT symptoms and its potentially lower accuracy during pregnancy (16). To address these knowledge gaps, we conducted a prospective diagnostic management outcome study for diagnosis of PE in pregnant women. We evaluated a diagnostic algorithm that included an assessment of pretest clinical probability using the revised Geneva score, a highly sensitive D-dimer test, bilateral CUS, CTPA, and a V/Q scan if results of CTPA were inconclusive (Figure 1). Figure 1. Diagnostic algorithm used in the study. CTPA= computed tomography pulmonary angiography; CUS= compression ultrasonography; PE= pulmonary embolism; V/Q= ventilationperfusion. Methods Study Population We conducted a multicenter, multinational, prospective diagnostic management outcome study. We screened outpatient pregnant women presenting at 1 of the participating centers with clinically suspected PE, defined as acute onset of new or worsening shortness of breath or chest pain without another obvious cause. Exclusion criteria were age less than 18 years, allergy to iodinated contrast agent, impaired renal function (defined as creatinine clearance <30 mL/min based on the CockcroftGault formula), diagnosis before presentation, indication for or current receipt of full-dose anticoagulation, and inaccessibility for follow-up. The study was performed in 2 countries (France and Switzerland), and 11 centers actively enrolled patients. The study was approved by the ethics committee according to legislation at each study site, and written informed consent was obtained from all participants. Diagnostic Work-up Pretest probability of PE was determined using the revised Geneva score. A D-dimer test was performed in all women by using the highly sensitive Vidas assay (bioMrieux). Pulmonary embolism was excluded in women who had low or intermediate pretest probability and a negative D-dimer result (<500 g/L). Women who had high pretest probability or a positive D-dimer result underwent bilateral CUS. The test was performed in a standard manner, with B-mode ultrasonography in transverse view and compression of the deep veins of the lower limbs (including the common femoral, femoral, popliteal, peroneal, and posterior tibial veins) along their whole length in the thigh and calf. We used the commonly accepted diagnostic criterion for DVT of lack of compressibility of a deep vein. When proximal DVT (popliteal vein or above) was found, PE was considered to be confirmed and no further testing was done. Women with a negative result on CUS underwent CTPA. The protocol for CTPA consisted of an evaluation of the pulmonary arteries up to and including the subsegmental vessels. Patients were examined while holding their breath or breathing shallowly, depending on the degree of dyspnea. Pulmonary embolism was considered to be present if contrast material outlined an intraluminal defect or if a vessel was totally occluded by low-attenuation material. Only multidetector CT machines were used. The acquisition parameters for CTPA were injection of a total volume of 100 mL of nonionic contrast material (iodine concentration, 300 to 350 mg/mL) with a power injector at 3 to 5 mL/s; imaging 9 to 20 seconds after initiation of the contrast material injection; scanning performed at 1.0 to 1.3 mm per section, with a pitch of 1.25 to 1.75, 120 kV, and 115 to 260 mA; and reconstruction of images at 0.6- to 0.8-mm intervals. If results of CTPA were inconclusive, a V/Q lung scan was performed, using 6 planar views and interpretation according to the PIOPED (Prospective Investigation Of Pulmonary Embolism Diagnosis) criteria. The complete diagnostic algorithm is depicted in Figure 1. Follow-up Patients with negative results on the diagnostic work-up were considered to not have PE, did not receive anticoagulant treatment, and had 3 months of clinical follow-up. They were instructed to contact the study team in case of new or worsening symptoms and were interviewed by telephone by the study coordinators at the end of follow-up using a standardized questionnaire. Whenever a possible event was disclosed, the clinical history, results of diagnostic tests, and clinic or admission reports were collected for adjudication. A 3-member independent adjudication committee reviewed all suspected VTE events, with blinding to the initial diagnostic work-up. Adjudication was based on full consensus. Outcomes The primary outcome was risk for adjudicated VTE events during the 3-month follow-up in women who did not receive anticoagulant therapy on the basis of negative results on the initial work-up. We calculated 95% CIs based on the Wilson score method without continuity correction (24) using an online calculator (25). Sample Size Estimation For the diagnostic strategy to be deemed safe, we determined a priori that the upper limit of the 95% CI around the estimate of 3-month VTE risk should not be higher than 3.0%. Hypothesizing a 5% prevalence of PE and a 1.5% 3-month thromboembolic risk after normal results on CTPA, we concluded that a sample of 300 patients would allow confirmation of the safety of the diagnostic strategy. Role of the Funding Source The funding sources had no role in the study design, interpretation of data, writing of the manuscript, or the decision to submit the manuscript for publication. Results Between August 2008 and July 2016, 441 pregnant women were screened. Seventeen declined to participate; 11 were unable to provide consent; 9 had testing for PE before being approached; 5 were allergic to contrast media; 1 was receiving long-term, full-dose anticoagulant treatment; 2 withdrew consent during the study; and 1 was not pregnant, leaving 395 who were included in the study. Characteristics of the included women are presented in Table 1. Seventeen were receiving prophylactic anticoagulation at inclusion, mainly for a previous VTE. The study flow chart is shown in Figure 2. Table 1. Characteristics of Included Patients* Figure 2. Study flow chart: intention-to-diagnose analysis. Three-month VTE risk among patients who did not receive anticoagulant treatment after negative results on the work-up was 0.0% (CI, 0.0% to 1.0%). CTPA= computed tomography pulmonary angiography; CUS= compression ultrasonography; PE= pulmonary embolism; V/Q= ventilationperfusion; VTE= venous thromboembolism. Pretest probability was low in 192 women (48.6%), intermediate in 200 (50.6%), and high in 3 (0.8%). Among the 392 women who did not have high pretest probability, 46 (11.7%) had a negative D-dimer result, 341 (87%) had a positive result, and 5 (1.3%) had no D-dimer testing. The proportion of negative D-dimer results decreased with increasing gestational age (21 of 83 [25.3%] during the first trimester, 19 of 170 [11.1%] during the second trimester, and 6 of 142 [4.2%] during the third trimester). Of note, 11 women underwent CTPA despite a negative D-dimer result; 10 had negative CTPA results, and 1 had an inconclusive result followed by a normal V/Q scan. Of the 349 women with a positive D-dimer result, no D-dimer test, or high pretest probability, 321 (92%) had negative results on CUS, 7 (2.0%) ha