Original article 375
The utility of the Wells clinical prediction model and ventilation-perfusion scanning for pulmonary embolism diagnosis in pregnancy Briony A. Cuttsa,b, Huyen A. Tranb, Eileen Merrimanb, Dee Nandurkarc, Gil Sooc, Dhruba DasGuptad, Nita Prassannana and Beverley J. Hunta Pulmonary embolism is one of the leading causes of mortality in pregnancy in the Western world. No clinical prediction models have been validated in pregnancy. As a result, any pregnant woman presenting with signs possibly consistent with pulmonary embolism is investigated radiologically. This study investigates whether using clinical prediction models for pulmonary embolism in pregnancy should be pursued in future prospective trials. The aim of this study was to retrospectively evaluate the Wells clinical prediction model and ventilation-perfusion scanning for pulmonary embolism in pregnancy. A retrospective study was performed on consecutive pregnant women who presented with suspected pulmonary emboli and underwent ventilation perfusion scanning at two tertiary institutions from 2007 until 2010. The clinical pretest probability was determined as likely or unlikely by two independent clinicians retrospectively using Wells-modified criteria. Scans were determined as normal, nondiagnostic or high probability for pulmonary emboli independently by two experienced radiologists. Disagreements were resolved by a third assessor independently. In 183 pregnant women, the pretest probability was determined as ‘pulmonary emboli likely’ in 76 (42%) and ‘pulmonary emboli unlikely’ in 107 (58%) of women. Scans were of high probability in four (2%),
Introduction Pulmonary embolism in pregnancy is the leading cause of maternal death in the western world and was the third leading cause of direct maternal deaths (17%) in the most recent Confidential Enquiries into Maternal deaths in the United Kingdom [1,2]. Pregnancy increases the risk of pulmonary embolism by five-fold owing to a high oestrogen state, increased clotting factors (V, VIII, IX, X and fibrinogen), reduced protein S, reduced fibrinolysis and increased venous stasis induced by foetal compression of pelvic veins [3]. Pulmonary embolism can be difficult to diagnose in pregnancy, as women often have chest pain and dyspnoea as part of normal physiological changes in pregnancy (including increased minute-ventilation, tidal volume and alveolar ventilation, as well as foetal-induced diaphragmatic displacement) [4]. Distinguishing which symptoms are attributable to normal physiology of pregnancy, other cause such as gastro-esophageal reflux or pneumonia, or possibly pulmonary embolism is difficult and dependent upon clinician expertise [5]. D-dimers rise progressively throughout pregnancy and normal cutoff values for D-dimer assays have not been validated in 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
nondiagnostic in six (3%) and normal in 173 (95%) of women. This gives the pretest probability using Wellsmodified criteria a sensitivity of 100% [95% confidence interval (CI) 0.4–1.0] and a negative predictive value of 100% (95% CI 0.96–1.0). A structured clinical model such as modified Wells criteria may be useful in pregnancy, but further prospective evaluation is required. Blood Coagul Fibrinolysis 25:375–378 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:375–378 Keywords: decision support techniques, pregnancy, probability, pulmonary embolism a
Thrombosis & Haemophilia Centre, Guy’s & St Thomas’ Trust, London, UK, Department of Haematology, cDepartment of Radiology & Nuclear Medicine, Monash Medical Centre, Claydon, Victoria, Australia and dDepartment of Nuclear Medicine, Guy’s & St Thomas’ Trust, London, UK
b
Correspondence to Beverley J. Hunt, MD, FRCP, FRCPath, Thrombosis and Haemophilia Centre, Guy’s and St Thomas’ Trust, Westminster Bridge Road, Lambeth, London SE1 7HY, UK E-mail: [email protected] Received 3 September 2013 Revised 13 November 2013 Accepted 1 December 2013
pregnancy [6]. As a result, algorithms used to diagnose pulmonary embolism in pregnancy will usually commence with an imaging modality [7]. Computed tomography pulmonary angiography (CTPA) and ventilation perfusion scanning (VQ scans) are the two modalities used to diagnose pulmonary embolism. However, rates of high-probability VQ scans are much lower in pregnancy than in the nonpregnant population (99%) for prediction of pulmonary embolism in the nonpregnant population [13]. However, it has never been prospectively validated in pregnancy. Ideally, prospective clinical studies are required to validate any clinical prediction models and/or biomarkers as reliable diagnostic tests in the investigation of women with suspected pulmonary embolism. However, such a study is infeasible because the number of individuals needed to enter the study, on the basis of the high rate of negative investigations we have found, require a sample size of over 4000 participants with suspected pulmonary embolism. We estimated that this would require 50 hospitals to run the study for 4 years, based on a recruitment rate of 50%. The costs of such a study would be many millions and seems unwieldy to run. Therefore, in this study, we retrospectively used the MWS score in antepartum women who have had VQ scans to exclude pulmonary embolism to determine if clinical prediction models have potential diagnostic validity.
Materials and methods This was a retrospective study performed at two tertiary centres with maternity units that have combined delivery rates of approximately 15 000 per year. This study adhered to audit guidelines set out by both institutions. All pregnant women who presented with suspected pulmonary embolism and were referred for VQ scans between 2007 and 2010 were included. The clinical pretest probability using Wells modified criteria (PTP) was determined as ‘unlikely’ or ‘likely’ by two independent assessors retrospectively by examining medical records at presentation (Table 1). VQ scans were determined as normal, nondiagnostic or high probability for pulmonary embolism independently by two blinded experienced radiologists. Disagreements were resolved
by a third assessor independently. D-dimers were also examined. D-dimers were performed using an automated immunoturbidometric method. The Innovance and HemosIL HS assays were used. Maternal outcome, specifically development of pulmonary embolism for the remainder of pregnancy or postpartum, was also checked in medical records. The PTP and VQ scan results were then correlated. The PTP was analysed for sensitivity, specificity, negative and positive predictive values.
Results A total of 216 women were referred for VQ scans and records were available for 183 (85%). The median age was 30 years (range, 18–44 years). The majority were in their third trimester of pregnancy (n ¼ 100) (55%) (Fig. 1). PTP was determined as ‘pulmonary embolism likely’ in 76 (42%), and ‘pulmonary embolism unlikely’ in 107 (58%) of women (Fig. 2). VQ scans were of high probability in four (2%), nondiagnostic in six (3%) and normal in 173 (95%) of women (Fig. 2). Women with high-probability VQ scans received anticoagulation. Two women not assessed as high-probability VQ scans were anticoagulated and treated for pulmonary embolism on the basis of clinical grounds. Both had nondiagnostic scans that were also nondiagnostic on CTPA. A total of 16 (9%) women had a PTP of six or greater, two of whom had high probability scans. The remaining 14 women all had normal scans with no evidence of pulmonary embolism on subsequent review. None of the women categorized as ‘pulmonary embolism unlikely’ by PTP had nondiagnostic scans or evidence of pulmonary embolism on followup. This gives the PTP using Wells-modified criteria a sensitivity of 100% [95% confidence interval (CI) 0.4–1.0], specificity of 60% (95% CI 0.52–0.67), a positive predictive value of 5% (95% CI 0.01–0.14) and a negative predictive value of 100% (95% CI 0.96–1.0). D-dimers were performed in 51 (27%) of women in total from both centres; three of nine women Fig. 1
% Pregnant women in each trimester 1st
12% 2nd
Wells criteria for determining pretest probability of pulmonary embolism.
Table 1 Criteria
Clinical symptoms of DVT (leg swelling, pain with palpation) Other diagnosis less likely than pulmonary embolism Heart rate >100 Immobilization (3 days) or surgery in the previous 4 weeks Previous DVT/PE Haemoptysis Malignancy
3rd Score 3 3 1.5 1.5 1.5 1 1
A score of 4 means PE is unlikely; a score >4 means PE is likely. DVT, deep vein thrombosis; PE, pulmonary embolism.
55%
33%
Percentage of women in each trimester assessed with Wells score and VQ scan. VQ, ventilation/perfusion.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Wells criteria for pulmonary embolism in pregnancy Cutts et al. 377
Fig. 2
Modified Well’s criteria and correlation with VQ scan 70 Normal 60
Non-diagnostic
50
High
40 30 20 10 0 PE Unlikely
PE Likely
Wells-modified pretest probability correlated with VQ scans. Bar graph showing PTP of women using modified Wells criteria and correlation with VQ scan assessment (in percentage). PTP, pretest probability.
in the first trimester had a value within the normal reference range, were classified as ‘pulmonary embolism unlikely’ and had normal VQ scans. All women in the second and third trimester had elevated levels.
Discussion Misdiagnosing pulmonary embolism in pregnancy can be potentially fatal with mortality rates approaching 30%. The diagnosis is also important for managing current and subsequent pregnancies, future use of oestrogen-containing therapies and thromboprophylaxis [5,14]. This study shows the incidence of high-probability VQ scans in this population of pregnant women to be 2%, consistent with other studies and reflects the difficulty of excluding pulmonary embolism in pregnancy on clinical grounds alone. The low rate of confirmed pulmonary embolism on VQ scans in pregnant women contrasts with that of the nonpregnant population of 15–20% and highlights the need for a prospectively validated clinical prediction model to allow clinicians to rule out pulmonary embolism during pregnancy, thereby minimizing exposure of mother and foetus to radiation of imaging modalities. To the best of our knowledge, our study is the first to retrospectively evaluate PTP in antepartum pregnant women who have had VQ scans for possible pulmonary embolism. The negative predictive value of pregnant women retrospectively classified as ‘pulmonary embolism unlikely’ is high at 100% and none of these women were documented as having pulmonary embolism throughout the remainder of their pregnancy. The main limitations of this study are that it is retrospective, unblinded and relatively small. Moreover, our determination of no further pulmonary embolism is based on
medical record documentation alone and has not been verified by medical imaging or patient contact. O’Connor et al. [15] recently published retrospective data using Wells score in pregnant and postpartum women who had CTPA performed to exclude pulmonary embolism, and reported that using a score of 6 or greater had a sensitivity and a negative predictive value of 100%. Although the use of a high score in PTP scoring models does not assist in determining which women can safely be excluded from imaging, the high negative predictive value using the same scoring system is consistent with our finding. These studies indicate that PTP models may have a future role in reducing diagnostic imaging rates in pregnant women classified as ‘pulmonary embolism unlikely’ and a large multicentre prospective trial to validate this is worth exploring. A little less than one-half of all women (42%) in our study were classified as ‘pulmonary embolism likely’ indicating that a substantial proportion of pregnant women present with nonspecific clinical symptoms and signs. This demonstrates the shortcomings of applying clinical prediction model scores in pregnancy that have been generated for the nonpregnant population [5]. Future trials may need to change scoring items to be more specific for pregnancy such as not including mild tachycardia, and changing leg swelling to unilateral leg swelling, given both of these findings can be physiologically normal in pregnancy. Chan et al. [16] used pregnancy-specific criteria (left leg swelling, and being in the first trimester) as part of three criteria to diagnose deep vein thrombosis in pregnancy and found a high negative predictive value of 98.5%. In our study, 3% of VQ scans were nondiagnostic and this means that women required further evaluation to exclude pulmonary embolism. However, this rate is much lower than CTPA, which is approximately 20% in pregnant women due to increased cardiac outputs interfering with images obtained [8]. In the recent study by O’Connor et al., there is no mention of nondiagnostic scan rates using CTPA. The advantage of CTPA, however, is its ability to demonstrate an alternate diagnosis if pulmonary embolism is excluded [7,8]. D-dimer levels were performed for 27% of pregnant women in this study and the results are consistent with previous findings that show increasing levels with gestation [17]. Interestingly, all of the levels within the normal range for these particular assays were in women in the first trimester, with all women in the second and third trimester having elevated levels. Chan et al. [18] postulated that using higher cut-off points in D-dimer assays may compensate for this phenomenon and enable use of the assay to stratify pregnant women with possible deep vein thrombosis. Four of five D-dimer assays showed improved specificity and sensitivity using this approach (range, 61–79% and range, 93–100%, respectively) [18].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
378 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 4
Our study indicates that there may be a role in using clinical prediction models to help risk-stratify which pregnant women with suspected pulmonary embolism require diagnostic imaging thereby minimizing radiation exposure during pregnancy. Future multicentre prospective trials should be undertaken to see whether clinical predictions models specific for pregnancy can be derived and validated.
7
8
9
10 11
Acknowledgements B.A.C. was supported by a Young Investigator grant funded from The Haemtology Society of Australia and New Zealand and AMGEN. Conflicts of interest
12
13
None of the authors have a conflict of interest.
References 1
2
3
4 5 6
Khan KS, Wojdyla D, Say L, Gulmezoglu Am, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367:1066–1074. Confidential enquiry into maternal and child health: saving mothers’ lives: reviewing maternal deaths to make motherhood safer; 2003-2005. The Seventh report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH; 2007. Pabinger I, Grafenhofer H. Thrombosis during pregnancy: risk factors, diagnosis and treatment. Pathophysiol Haemost Thromb 2002; 32:322– 324. Nelson-Piercy C. Respiratory disease. In: Handbook of obstetric medicine. 4th ed. London, UK: Informa Healthcare; 2010. pp. 57 Bourjeily G, Paidas M, Khalil H, Rosene-Montella K, Rodger M. Pulmonary embolism in pregnancy. Lancet 2010; 375:500–512. Morse M. Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis. J Thromb Haemost 2004; 2:1202–1204.
14
15
16
17
18
Fatima N, Uz Zaman M, Sajjad Z, Nashmi I. Pulmonary embolism in pregnancy: a diagnostic dilemma. Ann Nucl Med 2011; 25:603– 608. Revel MP, Cohen S, Sanchez O, Collignon MA, Thiam R, Redheuil A, et al. Pulmonary embolism during pregnancy: diagnosis with lung scintigraphy or CT angiography? Radiology 2011; 258:590–598. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost 2009; 101:428–438. Cook JV, Kyriou J. Radiation from CT and perfusion scanning in pregnancy. BMJ 2005; 331:350. Wells PS, Anderson DR, Rodger MA, Stiell I, Dreyer JF, Barnes D, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med 2001; 135:98–107. Chagnon I, Bounameaux H, Aujesky D, Roy PM, Gourdier AL, Cornuz J, et al. Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism. Am J Med 2002; 113:269–275. van Belle A, Buller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295:172– 179. Carson JL, Kelley MA, Duff A, Weg JG, Fulkerson WJ, Palevsky HI, et al. The clinical course of pulmonary embolism. N Engl J Med 1992; 326:1240– 1245. O’Connor C, Moriarty J, Walsh J, Murray J, Coulter-Smith S, Boyd W. The application of a clinical risk stratification score may reduce unnecessary investigations for pulmonary embolism in pregnancy. J Matern Fetal Neonatal Med 2011; 24:1461–1464. Chan W-S, Lee A, Spencer FA, Crowther M, Rodger M, Ramsay T, Ginsberg JS. Predicting deep venous thrombosis in pregnancy: out in ‘LEFt’ field? Ann Intern Med 2009; 151:85–92. Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005; 51:825–829. Chan WS, Lee A, Spencer FA, Chunilal S, Crowther M, Wu W, et al. Ddimer testing in pregnant patients: towards determining the next ’level’ in the diagnosis of deep vein thrombosis. J Thromb Haemost 2010; 8:1004– 1011.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
The utility of the Wells clinical prediction model and ventilation-perfusion scanning for pulmonary embolism diagnosis in pregnancy Briony A. Cuttsa,b, Huyen A. Tranb, Eileen Merrimanb, Dee Nandurkarc, Gil Sooc, Dhruba DasGuptad, Nita Prassannana and Beverley J. Hunta Pulmonary embolism is one of the leading causes of mortality in pregnancy in the Western world. No clinical prediction models have been validated in pregnancy. As a result, any pregnant woman presenting with signs possibly consistent with pulmonary embolism is investigated radiologically. This study investigates whether using clinical prediction models for pulmonary embolism in pregnancy should be pursued in future prospective trials. The aim of this study was to retrospectively evaluate the Wells clinical prediction model and ventilation-perfusion scanning for pulmonary embolism in pregnancy. A retrospective study was performed on consecutive pregnant women who presented with suspected pulmonary emboli and underwent ventilation perfusion scanning at two tertiary institutions from 2007 until 2010. The clinical pretest probability was determined as likely or unlikely by two independent clinicians retrospectively using Wells-modified criteria. Scans were determined as normal, nondiagnostic or high probability for pulmonary emboli independently by two experienced radiologists. Disagreements were resolved by a third assessor independently. In 183 pregnant women, the pretest probability was determined as ‘pulmonary emboli likely’ in 76 (42%) and ‘pulmonary emboli unlikely’ in 107 (58%) of women. Scans were of high probability in four (2%),
Introduction Pulmonary embolism in pregnancy is the leading cause of maternal death in the western world and was the third leading cause of direct maternal deaths (17%) in the most recent Confidential Enquiries into Maternal deaths in the United Kingdom [1,2]. Pregnancy increases the risk of pulmonary embolism by five-fold owing to a high oestrogen state, increased clotting factors (V, VIII, IX, X and fibrinogen), reduced protein S, reduced fibrinolysis and increased venous stasis induced by foetal compression of pelvic veins [3]. Pulmonary embolism can be difficult to diagnose in pregnancy, as women often have chest pain and dyspnoea as part of normal physiological changes in pregnancy (including increased minute-ventilation, tidal volume and alveolar ventilation, as well as foetal-induced diaphragmatic displacement) [4]. Distinguishing which symptoms are attributable to normal physiology of pregnancy, other cause such as gastro-esophageal reflux or pneumonia, or possibly pulmonary embolism is difficult and dependent upon clinician expertise [5]. D-dimers rise progressively throughout pregnancy and normal cutoff values for D-dimer assays have not been validated in 0957-5235 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
nondiagnostic in six (3%) and normal in 173 (95%) of women. This gives the pretest probability using Wellsmodified criteria a sensitivity of 100% [95% confidence interval (CI) 0.4–1.0] and a negative predictive value of 100% (95% CI 0.96–1.0). A structured clinical model such as modified Wells criteria may be useful in pregnancy, but further prospective evaluation is required. Blood Coagul Fibrinolysis 25:375–378 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Blood Coagulation and Fibrinolysis 2014, 25:375–378 Keywords: decision support techniques, pregnancy, probability, pulmonary embolism a
Thrombosis & Haemophilia Centre, Guy’s & St Thomas’ Trust, London, UK, Department of Haematology, cDepartment of Radiology & Nuclear Medicine, Monash Medical Centre, Claydon, Victoria, Australia and dDepartment of Nuclear Medicine, Guy’s & St Thomas’ Trust, London, UK
b
Correspondence to Beverley J. Hunt, MD, FRCP, FRCPath, Thrombosis and Haemophilia Centre, Guy’s and St Thomas’ Trust, Westminster Bridge Road, Lambeth, London SE1 7HY, UK E-mail: [email protected] Received 3 September 2013 Revised 13 November 2013 Accepted 1 December 2013
pregnancy [6]. As a result, algorithms used to diagnose pulmonary embolism in pregnancy will usually commence with an imaging modality [7]. Computed tomography pulmonary angiography (CTPA) and ventilation perfusion scanning (VQ scans) are the two modalities used to diagnose pulmonary embolism. However, rates of high-probability VQ scans are much lower in pregnancy than in the nonpregnant population (99%) for prediction of pulmonary embolism in the nonpregnant population [13]. However, it has never been prospectively validated in pregnancy. Ideally, prospective clinical studies are required to validate any clinical prediction models and/or biomarkers as reliable diagnostic tests in the investigation of women with suspected pulmonary embolism. However, such a study is infeasible because the number of individuals needed to enter the study, on the basis of the high rate of negative investigations we have found, require a sample size of over 4000 participants with suspected pulmonary embolism. We estimated that this would require 50 hospitals to run the study for 4 years, based on a recruitment rate of 50%. The costs of such a study would be many millions and seems unwieldy to run. Therefore, in this study, we retrospectively used the MWS score in antepartum women who have had VQ scans to exclude pulmonary embolism to determine if clinical prediction models have potential diagnostic validity.
Materials and methods This was a retrospective study performed at two tertiary centres with maternity units that have combined delivery rates of approximately 15 000 per year. This study adhered to audit guidelines set out by both institutions. All pregnant women who presented with suspected pulmonary embolism and were referred for VQ scans between 2007 and 2010 were included. The clinical pretest probability using Wells modified criteria (PTP) was determined as ‘unlikely’ or ‘likely’ by two independent assessors retrospectively by examining medical records at presentation (Table 1). VQ scans were determined as normal, nondiagnostic or high probability for pulmonary embolism independently by two blinded experienced radiologists. Disagreements were resolved
by a third assessor independently. D-dimers were also examined. D-dimers were performed using an automated immunoturbidometric method. The Innovance and HemosIL HS assays were used. Maternal outcome, specifically development of pulmonary embolism for the remainder of pregnancy or postpartum, was also checked in medical records. The PTP and VQ scan results were then correlated. The PTP was analysed for sensitivity, specificity, negative and positive predictive values.
Results A total of 216 women were referred for VQ scans and records were available for 183 (85%). The median age was 30 years (range, 18–44 years). The majority were in their third trimester of pregnancy (n ¼ 100) (55%) (Fig. 1). PTP was determined as ‘pulmonary embolism likely’ in 76 (42%), and ‘pulmonary embolism unlikely’ in 107 (58%) of women (Fig. 2). VQ scans were of high probability in four (2%), nondiagnostic in six (3%) and normal in 173 (95%) of women (Fig. 2). Women with high-probability VQ scans received anticoagulation. Two women not assessed as high-probability VQ scans were anticoagulated and treated for pulmonary embolism on the basis of clinical grounds. Both had nondiagnostic scans that were also nondiagnostic on CTPA. A total of 16 (9%) women had a PTP of six or greater, two of whom had high probability scans. The remaining 14 women all had normal scans with no evidence of pulmonary embolism on subsequent review. None of the women categorized as ‘pulmonary embolism unlikely’ by PTP had nondiagnostic scans or evidence of pulmonary embolism on followup. This gives the PTP using Wells-modified criteria a sensitivity of 100% [95% confidence interval (CI) 0.4–1.0], specificity of 60% (95% CI 0.52–0.67), a positive predictive value of 5% (95% CI 0.01–0.14) and a negative predictive value of 100% (95% CI 0.96–1.0). D-dimers were performed in 51 (27%) of women in total from both centres; three of nine women Fig. 1
% Pregnant women in each trimester 1st
12% 2nd
Wells criteria for determining pretest probability of pulmonary embolism.
Table 1 Criteria
Clinical symptoms of DVT (leg swelling, pain with palpation) Other diagnosis less likely than pulmonary embolism Heart rate >100 Immobilization (3 days) or surgery in the previous 4 weeks Previous DVT/PE Haemoptysis Malignancy
3rd Score 3 3 1.5 1.5 1.5 1 1
A score of 4 means PE is unlikely; a score >4 means PE is likely. DVT, deep vein thrombosis; PE, pulmonary embolism.
55%
33%
Percentage of women in each trimester assessed with Wells score and VQ scan. VQ, ventilation/perfusion.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Wells criteria for pulmonary embolism in pregnancy Cutts et al. 377
Fig. 2
Modified Well’s criteria and correlation with VQ scan 70 Normal 60
Non-diagnostic
50
High
40 30 20 10 0 PE Unlikely
PE Likely
Wells-modified pretest probability correlated with VQ scans. Bar graph showing PTP of women using modified Wells criteria and correlation with VQ scan assessment (in percentage). PTP, pretest probability.
in the first trimester had a value within the normal reference range, were classified as ‘pulmonary embolism unlikely’ and had normal VQ scans. All women in the second and third trimester had elevated levels.
Discussion Misdiagnosing pulmonary embolism in pregnancy can be potentially fatal with mortality rates approaching 30%. The diagnosis is also important for managing current and subsequent pregnancies, future use of oestrogen-containing therapies and thromboprophylaxis [5,14]. This study shows the incidence of high-probability VQ scans in this population of pregnant women to be 2%, consistent with other studies and reflects the difficulty of excluding pulmonary embolism in pregnancy on clinical grounds alone. The low rate of confirmed pulmonary embolism on VQ scans in pregnant women contrasts with that of the nonpregnant population of 15–20% and highlights the need for a prospectively validated clinical prediction model to allow clinicians to rule out pulmonary embolism during pregnancy, thereby minimizing exposure of mother and foetus to radiation of imaging modalities. To the best of our knowledge, our study is the first to retrospectively evaluate PTP in antepartum pregnant women who have had VQ scans for possible pulmonary embolism. The negative predictive value of pregnant women retrospectively classified as ‘pulmonary embolism unlikely’ is high at 100% and none of these women were documented as having pulmonary embolism throughout the remainder of their pregnancy. The main limitations of this study are that it is retrospective, unblinded and relatively small. Moreover, our determination of no further pulmonary embolism is based on
medical record documentation alone and has not been verified by medical imaging or patient contact. O’Connor et al. [15] recently published retrospective data using Wells score in pregnant and postpartum women who had CTPA performed to exclude pulmonary embolism, and reported that using a score of 6 or greater had a sensitivity and a negative predictive value of 100%. Although the use of a high score in PTP scoring models does not assist in determining which women can safely be excluded from imaging, the high negative predictive value using the same scoring system is consistent with our finding. These studies indicate that PTP models may have a future role in reducing diagnostic imaging rates in pregnant women classified as ‘pulmonary embolism unlikely’ and a large multicentre prospective trial to validate this is worth exploring. A little less than one-half of all women (42%) in our study were classified as ‘pulmonary embolism likely’ indicating that a substantial proportion of pregnant women present with nonspecific clinical symptoms and signs. This demonstrates the shortcomings of applying clinical prediction model scores in pregnancy that have been generated for the nonpregnant population [5]. Future trials may need to change scoring items to be more specific for pregnancy such as not including mild tachycardia, and changing leg swelling to unilateral leg swelling, given both of these findings can be physiologically normal in pregnancy. Chan et al. [16] used pregnancy-specific criteria (left leg swelling, and being in the first trimester) as part of three criteria to diagnose deep vein thrombosis in pregnancy and found a high negative predictive value of 98.5%. In our study, 3% of VQ scans were nondiagnostic and this means that women required further evaluation to exclude pulmonary embolism. However, this rate is much lower than CTPA, which is approximately 20% in pregnant women due to increased cardiac outputs interfering with images obtained [8]. In the recent study by O’Connor et al., there is no mention of nondiagnostic scan rates using CTPA. The advantage of CTPA, however, is its ability to demonstrate an alternate diagnosis if pulmonary embolism is excluded [7,8]. D-dimer levels were performed for 27% of pregnant women in this study and the results are consistent with previous findings that show increasing levels with gestation [17]. Interestingly, all of the levels within the normal range for these particular assays were in women in the first trimester, with all women in the second and third trimester having elevated levels. Chan et al. [18] postulated that using higher cut-off points in D-dimer assays may compensate for this phenomenon and enable use of the assay to stratify pregnant women with possible deep vein thrombosis. Four of five D-dimer assays showed improved specificity and sensitivity using this approach (range, 61–79% and range, 93–100%, respectively) [18].
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
378 Blood Coagulation and Fibrinolysis 2014, Vol 25 No 4
Our study indicates that there may be a role in using clinical prediction models to help risk-stratify which pregnant women with suspected pulmonary embolism require diagnostic imaging thereby minimizing radiation exposure during pregnancy. Future multicentre prospective trials should be undertaken to see whether clinical predictions models specific for pregnancy can be derived and validated.
7
8
9
10 11
Acknowledgements B.A.C. was supported by a Young Investigator grant funded from The Haemtology Society of Australia and New Zealand and AMGEN. Conflicts of interest
12
13
None of the authors have a conflict of interest.
References 1
2
3
4 5 6
Khan KS, Wojdyla D, Say L, Gulmezoglu Am, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367:1066–1074. Confidential enquiry into maternal and child health: saving mothers’ lives: reviewing maternal deaths to make motherhood safer; 2003-2005. The Seventh report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH; 2007. Pabinger I, Grafenhofer H. Thrombosis during pregnancy: risk factors, diagnosis and treatment. Pathophysiol Haemost Thromb 2002; 32:322– 324. Nelson-Piercy C. Respiratory disease. In: Handbook of obstetric medicine. 4th ed. London, UK: Informa Healthcare; 2010. pp. 57 Bourjeily G, Paidas M, Khalil H, Rosene-Montella K, Rodger M. Pulmonary embolism in pregnancy. Lancet 2010; 375:500–512. Morse M. Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis. J Thromb Haemost 2004; 2:1202–1204.
14
15
16
17
18
Fatima N, Uz Zaman M, Sajjad Z, Nashmi I. Pulmonary embolism in pregnancy: a diagnostic dilemma. Ann Nucl Med 2011; 25:603– 608. Revel MP, Cohen S, Sanchez O, Collignon MA, Thiam R, Redheuil A, et al. Pulmonary embolism during pregnancy: diagnosis with lung scintigraphy or CT angiography? Radiology 2011; 258:590–598. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis, management and prevention. Thromb Haemost 2009; 101:428–438. Cook JV, Kyriou J. Radiation from CT and perfusion scanning in pregnancy. BMJ 2005; 331:350. Wells PS, Anderson DR, Rodger MA, Stiell I, Dreyer JF, Barnes D, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med 2001; 135:98–107. Chagnon I, Bounameaux H, Aujesky D, Roy PM, Gourdier AL, Cornuz J, et al. Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism. Am J Med 2002; 113:269–275. van Belle A, Buller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295:172– 179. Carson JL, Kelley MA, Duff A, Weg JG, Fulkerson WJ, Palevsky HI, et al. The clinical course of pulmonary embolism. N Engl J Med 1992; 326:1240– 1245. O’Connor C, Moriarty J, Walsh J, Murray J, Coulter-Smith S, Boyd W. The application of a clinical risk stratification score may reduce unnecessary investigations for pulmonary embolism in pregnancy. J Matern Fetal Neonatal Med 2011; 24:1461–1464. Chan W-S, Lee A, Spencer FA, Crowther M, Rodger M, Ramsay T, Ginsberg JS. Predicting deep venous thrombosis in pregnancy: out in ‘LEFt’ field? Ann Intern Med 2009; 151:85–92. Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005; 51:825–829. Chan WS, Lee A, Spencer FA, Chunilal S, Crowther M, Wu W, et al. Ddimer testing in pregnant patients: towards determining the next ’level’ in the diagnosis of deep vein thrombosis. J Thromb Haemost 2010; 8:1004– 1011.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
