Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study

Editor:

Righini and colleagues (1) conclude that a diagnostic strategy based on assessment of clinical probability, D-dimer measurement, compression ultrasound and CT pulmonary angiography can safely rule out pulmonary embolism (PE) in pregnant women. We wish to draw the attention of readers to our recent larger Diagnosis of Pulmonary Embolism in Pregnancy (DiPEP) study, which challenges their conclusion.

DiPEP evaluated clinical probability scores (modified for pregnancy) and D-dimer assays in 181 pregnant/postpartum women with PE confirmed by imaging or post mortem, and 259 pregnant/postpartum women with PE ruled out after imaging (2). All the clinical probability scores had poor discriminant value for PE. Of particular note, the simplified revised Geneva score area (used by Righini et al) had an area under the receiver-operating characteristic (ROC) curve of 0.579 (95% confidence interval (CI) 0.526–0.632). The sensitivity and specificity (95% CI) of D-dimer measurements were similarly poor. Those taken as part of routine care in 168 of the study population were 88.4% (74.1–95.6) and 8.8% (4.7–15.6), and 69.8% (53.7–82.3) and 32.8% (24.8–41.9) respectively, using a higher pregnancy-specific threshold.

Our findings are compatible with those of Righini et al. In their cohort, PE was ruled out by clinical probability and D-dimer in only 46 cases. If clinical probability and D-dimer provided no diagnostic value, we would expect around 3 of these 46 cases to have PE, which is compatible with observing no events during 3-month follow-up despite no treatment. We therefore consider their study was underpowered to assess the utility of D-dimer and clinical probability in excluding PE in pregnancy.

Furthermore, decision analysis modelling in DiPEP (4) showed that a strategy of scanning all women with a suspected PE accrued more quality-adjusted life years (QALYs) and incurred fewer costs than any selective strategy based on clinical probability and was therefore the dominant strategy. A threshold analysis showed that a clinical decision rule to select women for imaging would need to have sensitivity exceeding 97.5% to be cost-effective compared with the non-selective use of scanning.

The clinical and social consequences of missed PE are potentially catastrophic, while the cost savings and reduced radiation associated with avoiding 46 scans across 11 centres over 8 years are trivial. We will therefore conclude that clinical probability scores and D-dimer assays are of poor utility in suspected PE in pregnancy and puerperium. Only imaging reliably rules out PE.

Steve Goodacre, Professor of Emergency Medicine, School of Health and Related Research, University of Sheffield, UK

Beverley Hunt, Professor of Thrombosis and Haemostasis, Guy’s & St Thomas’s NHS Foundation Trust, London, UK

Catherine Nelson-Piercy, Professor of Obstetric Medicine, Guy’s & St Thomas’s NHS Foundation Trust, London, UK

References:
1. Righini M, Robert-Ebadi H, Elias A, Sanchez O, Le Moigne E, Schmidt J, et al. Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study. Ann Intern Med. [Epub ahead of print] doi: 10.7326/M18-1670
2. Goodacre S, Horspool K, Nelson- Piercy C, Knight M, Shephard N, Lecky F, Thomas S, Hunt BJ, Fuller G, on behalf of the DiPEP research group. The DiPEP (Diagnosis of PE in Pregnancy) study: An observational study of the diagnostic accuracy of clinical assessment, D-dimer and chest x-ray for suspected pulmonary embolism in pregnancy and postpartum. BJOG [Epub ahead of print] https://doi.org/10.1111/1471-0528.15286
3. Hunt BJ, Parmar K, Horspool K, Shephard N, Nelson- Piercy C, Goodacre S, on behalf of the DiPEP research group. The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: An observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium. B J Haematol 2018:180;694–704.
4. Goodacre S, Horspool K, Shephard N, Pollard D, Hunt B J, Fuller G, Nelson-Piercy C, Knight M, Thomas S, Lecky F & Cohen J. Selecting pregnant or postpartum women with suspected pulmonary embolism for diagnostic imaging: the DiPEP diagnostic study with decision-analysis modelling. Health Technol Assess 2018;22(47)

The recent paper discussing a strategy for diagnosis of pulmonary angiography in pregnancy by Righini et al in our view has serious ethical limitations 1 . This was a study carried out in 11 centers in Switzerland and France- in large medical centers with access to MRI. Magnetic resonance-pulmonary angiography (MR-PA) is an attractive new method with the advantage of radiation avoidance without the use of nephrotoxic contrast agents..
We believe that the study should have examined the use of MR angiography as the diagnostic tool.
The complications of CT angiography include the use of iodinated contrast media injection with its known renal complications and allergic reaction, and the exposure to ionizing radiation with both the risk for teratogenesis and cancer induction . A recent Cochrane systematic review on diagnosis of pulmonary embolus in pregnancy reached the conclusion that there is a need for direct comparisons of diagnostic methods including MRI 2 . CT and MRI have a similar sensitivity and specificity for diagnosing pulmonary embolism(3). The performance of a CT in a pregnant woman raises concerns regarding exposure to both these risk factors. These are not insignificant factors and there is no mention for instance of placing a shield on the abdomen of the pregnant woman to decrease the exposure to radiation.
Pulmonary embolism can be confidently diagnosed by MR angiography and these facilities are available in developed European nations . In addition, we feel that a follow up period of 3 months is grossly inadequate for assessing the radiation effects on both the mother and the fetus. This follow up period was only for the control group in order to be certain that a thromboembolic event did not occur. There was no follow up for the patients who had radiation exposure.

The principles of good clinical practice state “Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. The rights, safety, and well-being of the trial subjects are the most important considerations” (https://ichgcp.net/2-the-principles-of-ich-gcp-2/ accessed 11/10/18).

References

Righini M, Robert_Ebadi H, Elias A, Sanchez O, Le Moigne E,Schmidt J et al. Diagnosis of pulmonary embolism during pregnancy:A multicenter prospective management outcome study. Ann Intern Med 2018; doi:10.7326/M18-1670.

2. Van Mens TE, Scheres LJ, De Jong PG, Leeflang MM, Nijkeuter M, Middeldrop S. Imaging for the exclusion of pulmonary embolism in pregnancy. Cochrane Database Syst Rev 2017:1:CD011053 doi:10.1002/14651858.CD0011053.pub2

3. Ohno Y, Higashino T, Takenaka D, Sugimoto K, Yoshikawa T, Kawai H et al. MR angiography with sensitivity encoding (SENSE) for suspected pulmonary embilism:Comparison with MDCT and ventilation-perfusion scintigraphy. AJR 2004;183:91-8.

We respectfully disagree with Drs. Malnick and Kikayon. Limited research on the diagnostic performance of magnetic resonance (MR) imaging for diagnosing pulmonary embolism (PE) has been reported.1,2 Specifically, a sensitivity of around 75% has been reported which is not acceptable for a potentially fatal disease such as PE.3 No prospective management outcome studies confirmed the safety of ruling out PE on the basis of a negative MR angiography to date, let alone pregnant women. As a result, none of the available clinical practice guidelines support the use of MRA for PE diagnosis.4,5
Reducing exposure to radiation for the mother and the fetus is certainly important. However, there is general consensus, which is supported by international recommendations, that the risks of undiagnosed PE or inappropriate anticoagulation far outweigh any risk from diagnostic imaging in pregnant women. Therefore, it is crucial to definitely confirm or rule out PE by using validated diagnostic algorithms and tools. Until further evidence becomes available, we strongly recommend against the use of MRA in this indication.



1. Zhou M, Hu Y, Long X, et al. Diagnostic performance of magnetic resonance imaging for acute pulmonary embolism: a systematic review and meta-analysis. J Thromb Haemost 2015;13:1623-34.
2. Stein PD, Chenevert TL, Fowler SE, et al. Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III). Ann Intern Med 2010;152:434-43, W142-3.
3. Revel MP, Sanchez O, Couchon S, et al. Diagnostic accuracy of magnetic resonance imaging for an acute pulmonary embolism: results of the 'IRM-EP' study. J Thromb Haemost 2012;10:743-50.
4. Wan T, Skeith L, Karovitch A, Rodger M, Le Gal G. Guidance for the diagnosis of pulmonary embolism during pregnancy: Consensus and controversies. Thromb Res 2017;157:23-8.
5. Konstantinides SV. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014;35:3145-6.

We read with interest the comment regarding our recently published paper on pulmonary embolism (PE) diagnosis in pregnant patients.1 We highlight that our study is the first prospective management outcome study in the field. In contrast, the DiPEP study was a retrospective analysis of two cohorts (one of women with suspected PE recruited in 11 centers, and one of women with confirmed PE across the UK), including a mix of pregnant and post-partum women. In the DiPEP study, different D-dimer assays with different thresholds were used.2 The timing of D-dimer testing was not specified, but most women were already started on anticoagulant therapy at the time of testing. Also, the final comparator to assess the diagnostic performance of D-dimer was the presence or the absence of PE, which was based on clinical grounds in around 15% of patients. Therefore, there are potentially important limitations in the inferences reported in the DiPEP study.
We agree that our study does not provide a definitive conclusion on the safety of D-dimer testing during pregnancy either, given the wide confidence interval around the estimates of the three-month risk of venous thromboembolism (VTE). However, our study is the first prospective management cohort in which pretest probability assessment and D-dimer were used to exclude PE. Moreover, our results should be interpreted in the context of previous data on the use of D-dimer to rule out suspected VTE in pregnancy.3 Moreover, we strongly believe that there is value in trying to avoid radiation during pregnancy, even if only in one in ten patients. The results of the ARTEMIS (NTR 5913) study are awaited soon and should provide further data on the use of D-dimer to rule out PE in this population.

1. Righini M, Robert-Ebadi H, Elias A, et al. Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study. Ann Intern Med 2018.
2. Hunt BJ, Parmar K, Horspool K, et al. The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: An observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium. Br J Haematol 2018;180:694-704.
3. Chan WS, Chunilal S, Lee A, Crowther M, Rodger M, Ginsberg JS. A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy. Ann Intern Med 2007;147:165-70.