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Clinical Opinion

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New directions in the diagnosis and treatment of pulmonary embolism in pregnancy


Briony A. Cutts, B Med MD; Dhruba Dasgupta, MBBS, BSc, FRCR, MSc; Beverley J. Hunt, FRCP FRCPath, MD shortness of breath, determination of normal pregnant from PE symptoms may be difcult. The number of mothers who are imaged to exclude PE as a result of those symptoms is high, which reects clinicians fear of fatal misdiagnosis. The low incidence of high-probability V/Q scans in the pregnant, compared with nonpregnant, population (5% vs 1520%) illustrates this.2,6,13 Rodger et al14 showed that interobserver reliability was improved with the use of clinical prediction models vs clinical judgment alone. A retrospective assessment by OConnor et al15 that studied the usefulness of the modied Wells score of 125 mothers with suspected PE who had a helical computed axial tomographic pulmonary angiography (CTPA) found sensitivity and specicity levels of 100% and 90%, respectively, using a score of 6. However, this does not address how to differentiate low- from intermediaterisk pregnant women and who can be excluded from diagnostic imaging, perhaps because of the criterion within the Wells score of an alternative diagnosis that is at least as likely as that of PE. This criterion contributes substantially to the nal score, is open to interpretation, and is dependent on clinical expertise.16 There have been no prospective trials that have validated clinical prediction models to exclude PE in pregnancy. Biomarkers D-dimers are plasma break-down products of cross-linked brin and therefore are used as markers of recent thrombus formation. Unfortunately, D-dimers are also elevated in malignancy or acute inammatory states; therefore, they are used for their negative predictive value (ie, a normal value excludes VTE).17 They can be measured by a number of methods that enable rapid clinical turnaround. Highly sensitive D-dimer assays with a cutoff value of 0.5 g/mL will exThe diagnosis and management of pulmonary embolism in pregnancy is difcult, because diagnostic procedures and the use of anticoagulants potentially can expose mother and fetus to adverse effects. This article reviews evidence for current best practice and emerging novel techniques for the diagnosis of pulmonary embolism in pregnancy and includes clinical prediction models, biomarkers, and diagnostic imaging that may offer improvement in the diagnosis and investigation of pulmonary embolism in pregnancy in the future. The usefulness of new anticoagulant agents (fondaparinux, rivaroxaban, and dabigatran) in managing pulmonary embolism in future pregnancies is also explored. Key words: pregnancy, pulmonary embolism, thrombosis

enous thromboembolism (VTE) remains a major cause of maternal death. Despite widespread thromboprophylaxis use, it was the third highest cause of direct maternal death in the recent UK Condential Enquiries into Maternal Deaths (17% of direct maternal deaths).1 The diagnosis of pulmonary embolism (PE) in pregnancy is difcult; a balance of maternal and fetal radiation exposure against potentially fatal misdiagnosis is required.2 In pregnancy, prospective clinical predictive models have not been validated, and D-dimer assays are said not to be useful because of physiologically increasing levels throughout gestation with a resultant increased reliFrom the Thrombosis and Haemophilia Centre (Drs Cutts and Hunt) and the Department of Nuclear Medicine (Dr Dasgupta), Guys and St Thomas Trust, London, UK. Received January 27, 2012; revised June 11, 2012; accepted June 15, 2012. Supported in part by a Young Investigator grant from the Haemotology Society of Australia and New Zealand (B.A.C.). The authors report no conict of interest. Reprints: Beverley J. Hunt, MD, Thrombosis and Haemophilia Centre, Guys and St Thomas NHS Foundation Trust, Westminster Bridge Rd., London SE1 7EH, UK. Beverley.Hunt@gstt.nhs.uk.
0002-9378/$36.00 Crown Copyright 2013 Published by Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2012.06.035

ance on imaging to exclude PE.3-6 Validated clinical prediction models combined with biomarkers that are specic for pregnancy may (1) enable risk stratication, (2) reduce the number of patients whose condition requires imaging, and (3) reduce percentages of fetomaternal radiation exposure.2,5,6 If risk stratication is not possible, then imaging modalities with higher sensitivity and specicity and lower radiation risk are required. We will discuss the use of 3dimensional nuclear medicine ventilation and perfusion single photon emission computed tomography (V/QSPECT), an exciting new imaging modality.7,8 In the past decade, new anticoagulants have been developed, and their potential role in pregnancy will be explored.

New directions in diagnosis Clinical prediction models In the nonpregnant population, validated clinical predictive models such as the modied Wells score stratify likely PE from unlikely PE to exclude patients from potentially harmful diagnostic imaging (Table 1).9,10 Combined with a negative D-dimer, the negative predictive value is 99.5%.11 Pregnancy confers a 5-fold increased risk of VTE because of venous stasis, a prothrombotic state caused by increased levels of coagulation factors, reduced protein S, and brinolytic activity.12 When pregnant women have chest symptoms such as pain and

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clude acute PE in nonpregnant patients when combined with unlikely PE stratication with the use of modied Wells score criteria.9-11 In pregnancy, D-dimers rise throughout gestation, drop rapidly after delivery, and return to normal 4-6 weeks after delivery. The standard cutoff value of 0.5 g/mL for D-dimers shows their limited usefulness in pregnancy. Kline et al18 found that, of 50 pregnant women, none had a Ddimer concentration of 0.50 g/mL by the third trimester. A case report of a negative D-dimer concentration in a pregnant woman with PE who was subsequently diagnosed on imaging also exists.19 Chan et al20 hypothesized that higher cut-off points for the diagnosis of deep venous thrombosis (DVT) may compensate for the higher baseline D-dimer values that are seen in pregnancy. Five D-dimer assays that diagnose DVT in symptomatic mothers were tested and, with the use of receiver operating curves, showed improved specicity (range, 6179%) and a small reduction in sensitivity in 4 of the 5 assays (range, 93100%). This approach has not been assessed to exclude PE in pregnancy. Brain natriuretic peptide (BNP) is a natriuretic hormone that is released from cardiac ventricles. Pro-hormone cleavage produces N-terminal pro-BNP (NT-pro-BNP). Cardiac troponin I and T are cardiac-specic proteins. All become elevated in cardiac damage and failure.21,22 Recent metaanalyses show that death in nonpregnant patients with PE is predicted by raised serum troponin and NT-pro-BNP levels; predicted death from acute PE is 33% if both are elevated.23 BNP levels double during pregnancy but remain stable irrespective of gestation.24 Tanous et al25 showed that women with preexisting cardiac disease had further elevation of BNP levels in pregnancy and that rising BNP levels predated events or decompensation in 88% of mothers. A level of 100 pg/mL had a negative predictive value of 100% for gestational cardiac events. The use of troponin I levels as a marker of right heart strain in pregnancy have not been studied and require validation. Serum BNP or NT-pro-BNP levels are an attrac-

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tive option for clinical trials of risk-stratication models for PE in pregnancy. Imaging Various diagnostic algorithms to exclude PE in pregnancy exist (Figure 1); however, most mothers will require radiologic imaging.2,6 A correct diagnosis is essential because missing a PE can be fatal; a false-negative result has shortand long-term management implications for anticoagulation in current and subsequent pregnancies. The modalities that are used most frequently are V/Q scans and/or CTPA in conjunction with lower limb compression Doppler ultrasonography. V/Q scans take planar images of patient lungs after inhalation and injection with a radioactive isotope. Pulmonary arterial thrombus is identied by areas of mismatched perfusion compared with ventilation. Low-dose perfusion scans have comparable detection rates for PE in pregnancy, with no statistically signicant difference between the number of positive, nondiagnostic, or normal scans compared with CTPA.26,27 Unfortunately, approximately 20% of women who undergo imaging with CTPA require further imaging because of initial nondiagnostic scans; however, most centers have 24-hour accessibility, unlike nuclear medicine imaging, which depends on isotope supply.26 CTPA can also visualize emboli directly, diagnose alternative disease, and deliver a lower dose of fetal radiation. Its main drawbacks are poor vessel opacication because of physiologic higher cardiac outputs in pregnancy and high doses of radiation to maternal breast tissue.27 Compression Doppler ultrasonography is a safe and accessible modality, but imaging of pelvic DVT in pregnancy can be difcult because the uterus obscures imaging. If compression Doppler ultrasonography shows a DVT, then chest symptoms are assumed to be due to PE, and no further imaging is required.28 The fear that is associated with fetal radiation exposure has been over-stated.29 Low-dose radiation, dened as exposure of 50 mSv, does not increase fetal or infant death or cause mental defects or growth retardation at 8-15 weeks gestation; however, a small increase of child-

Clinical Opinion

TABLE 1

Wells criteria for pretest probability for pulmonary embolism and diagnostic algorithm for MWS
Criteria Clinical symptoms of deep venous thrombosis (leg swelling, pain with palpation) Other diagnosis less likely than pulmonary embolism Heart rate, 100 mm Hg Score 3

...........................................................................................................

3 1.5

........................................................................................................... ...........................................................................................................

Immobilization (3 days) or surgery in the previous 4 days Previous deep venous thrombosis/pulmonary embolism Haemoptysis Malignancy

1.5 1.5

...........................................................................................................

........................................................................................................... ...........................................................................................................

1 1

...........................................................................................................

MWS 4 pulmonary embolism unlikely no diagnostic imaging required. MWS 4 pulmonary embolism likely diagnostic imaging required. MWS, modied Wells score. Cutts. PE in pregnancy. Am J Obstet Gynecol 2013.

hood malignancy (1:5000), increased heterochromia, and a mild preponderance of male sex have been seen.29 Radiation exposure to the fetus with both V/Q scans and CTPA is 1-2 mSv. V/Q scanning has comparable exposure to CTPA, although perfusion-only scanning decreases this further (Table 2).29 During the consent procedure in the past, radiologists focused on fetal radiation exposure and neglected to inform mothers of radiation exposure to maternal breast tissue. Perfusion-only scanning delivers a dose of 0.28 mSv to maternal breast tissue, but CTPA gives a dose 35 times higher at 10-70 mSv. In the long-term, CTPA confers a 14% increased risk against the background for breast cancer in pregnant women who are 40 years old.30,31 This exposure can be halved with the use of bismuth shielding.32 Disadvantages of current imaging modalities means other diagnostic procedures such as magnetic resonance imaging (MRI; which is noninvasive and does not require radiation exposure) are appealing in pregnancy.33 MRI direct thrombus imaging requires no contrast 103

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Clinical Opinion
FIGURE 1

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Diagnostic algorithm used for the management of possible PE in pregnancy at our institution
Symptoms of PE

Doppler US

Thrombosis present

Normal

Treat

CXR

Normal

Abnormal

Perfusion only Scan

CTPA

Thrombosis present Thrombosis present Normal Non-Diagnostic

Yes

PE Excluded

No

Yes

Treat
Cutts. PE in pregnancy. Am J Obstet Gynecol 2013.

PE Excluded

Treat

CTPA, computed axial tomographic pulmonary angiography; CXR, chest x-ray; PE, pulmonary embolism; US, ultrasound scanning.

agent but depends on inherent thrombus qualities. Red cells that are trapped in venous clot become hypoxic and produce methemoglobin with resultant reduced T1 signaling. It has shown value in the detection of DVT but has not been validated for PE and requires an experienced interpreter.34 Magnetic resonance angiogram detects central and segmental emboli accurately but is less able to detect smaller subsegmental emboli. It also requires gadolinium contrast, which has not been veried as safe in human pregnancy, although it has been used to diag104

nose placenta accreta and leiomyoma with no fetal side-effects.35 High-dose gadolinium produced fetal growth retardation in mice, but clinically relevant doses showed no fetal teratogenic effects.35 Maternofetal pharmacokinetics of high-dose gadolinium in mice found the maximal gadolinium fetal concentration at 30 minutes after injection with undetectable level within 24 hours in the fetus and within 48 hours in amniotic uid.36 Unfortunately, such studies in humans are unethical. Real-time MRI with fast imaging steady-state precession

reduces artifact caused by motion by delivering rapid radiofrequency excitation pulses that minimize the usual signal decay time for T1 or T2 signals that causes magnetization to obtain a steady state. It does not require the use of gadolinium, and initial trials show promise but require further validation.37 The European Association of Nuclear Medicine recently has published data on V/QSPECT imaging. In contrast to the 2-dimensional image from standard V/Q scanning, multiple 3-dimensional images are acquired because the scanner

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Clinical Opinion

TABLE 2

Maternofetal radiation exposure with different imaging modalities for pulmonary embolism in pregnancy
Procedure Chest x-ray Perfusion lung scanning 99-m Technetium macroaggregates to human albumin Low dose: 40 MBq High dose: 200 MBq Estimated fetal radiation exposure (millisievert)a 0.01 Estimated maternal radiation exposure to breast tissue (millisievert) 1.00

................................................................................................................................................................................................................................................................................................................................................................................

....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................

0.11-0.20 0.20-0.60

0.28-0.50 1.20

................................................................................................................................................................................................................................................................................................................................................................................

Ventilation 99-m Technetium aerosol

................................................................................................................................................................................................................................................................................................................................................................................

0.10-0.30

0.01 2.50 2.50 0.05

Computed tomography pulmonary angiography multidetector Ventilation and perfusion single photon emission computed tomography (V/QSPECT) Background radiation from living 1 year in London, UK Radiation from long-haul international air ight
N/A, not applicable. Data reproduced, with permission, from Chunilal29 and Bajc et al.8
a

................................................................................................................................................................................................................................................................................................................................................................................

0.24-0.66

10-70

1.90 N/A N/A

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Fifty millisievert is equivalent to 5 rads or 50 mGy.

Cutts. PE in pregnancy. Am J Obstet Gynecol 2013.

rotates around the patient. This results in better image quality and fewer nondiagnostic scans and is faster than regular planar V/Q imaging (Figure 2).7,8 Two studies found V/QSPECT to have a higher sensitivity and specicity compared with planar V/Q: 97% and 91%, compared with 76% and 85%, respectively.8,38 Excitingly, V/QSPECT has higher rates of sensitivity (97% vs 68-86%) and comparative rates of specicity when compared with CTPA.39,40 The radiation dose with V/QSPECT is approximately 3540% of the dose that is required for CTPA with a slightly lower radiation dose to the fetus and a signicantly lower dose to maternal breast tissue (approximately 4% of CTPA).41 CTPA can be inconclusive in approximately 25% of women, whereas V/QSPECT was inconclusive in 1% of cases.27,41 Efcacy in the determination of differential diagnoses, which include pneumonia and heart failure, was also seen. Its main disadvantage is a limitation to the access of appropriate radioactive isotopes. The current recommendation by the European Association of Nuclear Medicine is that V/QSPECT become the gold standard for the diagnosis of PE in all patients (pregnant and nonpregnant) and should be used in preference to CTPA.8

New directions in treatment New anticoagulant agents Clinical trials to establish best practice for treatment of VTE in pregnancy are lacking; thus, treatment with current

anticoagulants has been extrapolated from trials in nonpregnant populations. Treating VTE with vitamin K antagonists in pregnancy is avoided preferably because warfarin embryopathy causes

FIGURE 2

V/QSPECT for the detection of pulmonary embolism


Perfusion

Ventilation

V/QSPECT thermal imaging coronal posterior sections in a female patient show multiple large pulmonary-ventilatory areas of mismatch that indicate pulmonary emboli that involve the upper and lower lobes of the right lung (white arrows).
V/QSPECT, ventilation and perfusion single photon emission computed tomography. Cutts. PE in pregnancy. Am J Obstet Gynecol 2013.

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icting data about whether doses correlate with anti-Xa levels.48,49 Moreover, the UK quality program showed enormous variation between hospital laboratories when a sample spiked with LMWH was sent out for evaluation of anti-Xa activity.50 Whether the alteration of doses to maintain anti-Xa levels within a theoretic target window impacts clinical outcomes, which include recurrent VTE and hemorrhage, is unknown. LMWH has a lower incidence of heparininduced thrombosis compared with unfractionated heparin. Indeed in pregnancy, no cases of heparin-induced thrombosis because of LMWH have been published.46 The bleeding risk is also low; in a systematic review of 64 studies that involved 2777 pregnancies, the overall frequency of bleeding was 1.98% (95% condence interval, 1.502.57%).51 Osteoporosis is a known complication of unfractionated heparin, but only a handful of cases have been described with the use of LMWH throughout pregnancy.52 Thus, despite the lack of clinical trials studying the efcacy of LMWH in thromboprophylaxis in pregnancy, it is used widely and perceived as to be safe. However, the use of LMWH for treatment of VTE in pregnancy has been studied inadequately and should not be considered so benevolently.46,47 In the last 5 years, new anticoagulants have been developed; their usefulness of treating PE in pregnancy is discussed later. Fondaparinux Fondaparinux is a synthesized derivative of the natural pentasaccharide within heparin. It shows high-afnity reversible binding to antithrombin that causes conformational change with enhanced factor Xa inactivation. It has a longer half-life of 17 hours when compared with the half-life of approximately 12 hours for LMWH.53 There is limited experience with its use in pregnancy (mainly animal studies and a few human case reports), so it is used as an alternative anticoagulant. There is a lack of clarity of its ability to cross the placenta. Dempe54 reported drug cord blood levels one-tenth of maternal levels using antiXa and activated partial thromboplastin

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time assays that indicated minor transplacental passage of the drug. However, Knol et al55 documented no fetal hemorrhages or anomalies in 12 pregnant women who received treatment doses of 7.5-mg fondaparinux daily; median delivery blood loss was 450 mL with 3 signicant (1000 mL) postpartum hemorrhages occurring, 2 within 12 hours of the last injection. From limited data fondaparinux appears efcacious in pregnancy, but bleeding risk is not absent, and care is required when used as second-line therapy. The new oral anticoagulants There are a number of new, exciting oral anticoagulants coming that have predictable pharmacokinetics so that, unlike vitamin K antagonists, they do not require monitoring. At the vanguard are rivaroxaban and dabigatran followed by apixiban and endoxaban, among others. Rivaroxaban is a direct factor Xa inhibitor, and dabigatran is a direct thrombin inhibitor. Worldwide both have been licensed for VTE prophylaxis after hip and knee replacement and are licensed or awaiting license for stroke prevention in atrial brillation and for secondary VTE prevention.56-60 However, there are no data for the use of either agent in human pregnancy. Animal studies with both drugs have found teratogenic effects, reduced fetal viability, hemorrhagic changes, and placental abnormalities. Rivaroxaban is secreted in breast milk, but no such data exists for dabigatran.61,62 For these reasons, dabigatran or rivaroxaban cannot be recommended for use in pregnancy, and women who take these drugs and wish to conceive are advised to change to a vitamin K antagonist and then LMWH, depending on their underlying problem. Thrombolysis, graduated compression stockings, and inferior venacaval lters Postthrombotic syndrome develops in 80% of pregnant women after DVT. Grade II graduated compression stockings (ankle pressure, 30-40 mm Hg) for 2 years after diagnosis reduces the incidence of postthrombotic syndrome.63 There is minimal experience of thrombolysis of PE in pregnancy. Case reports

nasal hypoplasia and epiphysis stippling during the rst trimester.42 In the second and third trimester, there is increased risk of fetal intracranial hemorrhage, spontaneous abortion, stillbirth, ventricular septal defects, and growth retardation, especially with maternal warfarin doses of 5 mg.43 Warfarins transplacental passage results in a higher international normalized ratio in the fetus than in the mother because the fetal liver fails to metabolize vitamin K and warfarin as effectively as an adult liver.42 Low molecular weight heparins (LMWHs) are the anticoagulants of choice in pregnancy because they do not cross the placenta.44 LMWHs act by potentiating antithrombin 10,000-fold; their main effect is through anti-Xa activity. Unlike unfractionated heparin, they have reliable pharmacokinetics (ie, dose has a linear relationship anti-Xa activity).45 LMWHs are cleared renally and so, in pregnancy, have a shorter half-life with improved creatinine clearance.46 This combined with the increased plasma volumes of pregnancy reduce peak drug concentrations and shorten the half-life.45,46 Unfortunately, existing twice daily dosing recommendations in the Royal College of Obstetricians and Gynaecologists guidelines (no. 37b) for treatment of VTE in pregnancy are extrapolated from thromboprophylactic data only.47 Knight et al44 reviewed the UK obstetric surveillance data and found that a variety of onceand twice-daily dosing regimens existed. Because of the reliable pharmacokinetics of LMWH in nonpregnant patients, the monitoring of anti-Xa levels is reserved for the elderly, extremes of bodyweight, and impaired renal clearance.47 No published data exists to support recommendations in the Royal College of Obstetricians and Gynaecologists guidelines to test anti-Xa levels in pregnant women at extremes of bodyweight and renal impairment.45 A 3-hour postdose peak level of 0.4-1.2 unit/mL is considered within the therapeutic range by 1 expert, but this is not supported by clinical trials because few studies of dosage and the monitoring of anti-Xa levels in the pregnant population exist.42 Those investigators who have studied thromboprophylactic doses show con106

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show its use in women who are compromised hemodynamically from PE. Hemorrhagic complication rates are similar to nonpregnant patients with pregnancy-related complications that include placental abruption and documented preterm labor.64 A fresh DVT (ie, after 37 weeks gestation), especially in the pelvis or proximal veins, has a likelihood of embolization during labor, possibly made more so by anticoagulation withdrawal in labor. Temporary retrievable inferior venacaval lters are used most appropriately in this setting.2,65

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5. Chan WS, Ray JG, Murray S, Coady GE, Coates G, Ginsberg JS. Suspected pulmonary embolism in pregnancy: clinical presentation, results of lung scanning, and subsequent maternal and pediatric outcomes. Arch Intern Med 2002;162:1170-5. 6. Fatima N, uz Zaman M, Sajjad Z, Hashmi I. Pulmonary embolism in pregnancy: a diagnostic dilemma. Ann Nucl Med 2011;25:603-8. 7. Bajc M. Value of ventilation/perfusion SPECT detecting extensive pulmonary embolism in a patient with pneumonia. Thromb Haemost 2005;93:993-4. 8. Bajc M, Neilly JB, Miniati M, Schuemichen C, Meignan M, Jonson B. EANM guidelines for ventilation/perfusion scintigraphy: part 1, pulmonary imaging with ventilation/perfusion single photon emission tomography. Eur J Nucl Med Mol Imaging 2009;36:1356-70. 9. Perrier A, Desmarais S, Miron MJ, et al. Noninvasive diagnosis of venous thromboembolism in outpatients. Lancet 1999;353:190-5. 10. Wells PS, Anderson DR, Rodger MA, 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. 11. Wells PS, Anderson DR, Rodger M, 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 Int Med 2001;135:98-107. 12. Pabinger I, Grafenhofer H. Thrombosis during pregnancy: risk factors, diagnosis and treatment. Pathophysiol Haemost Thromb 2002;32: 322-4. 13. PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263:2753-9. 14. Rodger MA, Maser E, Stiell I, Howley HE, Wells PS. The interobserver reliability of pretest probability assessment in patients with suspected pulmonary embolism. Thromb Res 2005;116:101-7. 15. OConnor C, Moriarty J, Walsh J, Murray J, Coulter-Smith S, Boyd W. The application of a clinical risk stratication score may reduce unnecessary investigations for pulmonary embolism in pregnancy. J Matern Fetal Neonatal Med 2011;24:1461-4. 16. Bounameaux H, Perrier A, Righini M. Diagnosis of venous thromboembolism: an update. Vasc Med 2010;15:399-406. 17. Crippa L, DAngelo SV, Tomassini L, Rizzi B, DAlessandro G, DAngelo A. The utility and cost-effectiveness of D-dimer measurements in the diagnosis of deep vein thrombosis. Haematologica 1997;82:446-51. 18. Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy:

Clinical Opinion

Future directions Clinical trials are needed to improve the management of PE in pregnancy. Existing clinical prediction models require prospective validation in pregnancy. Do biomarkers such as high cutoff D-dimers and BNP in conjunction with clinical prediction models exclude lowrisk women and thus reduce the risk of maternofetal radiation exposure? Certainly V/QSPECT is a major advance, and the latest magnetic resonance imaging technology requires trials to investigate rates of sensitivity and specicity in pregnancy. Given the altered pharmacokinetics of LMWH in pregnancy, future trials that will identify optimal dosing regimens for the treatment of VTE and the study of maternal and fetal outcomes in women are needed. Finally, new oral anticoagulant agents cannot be recommended for use in pregnancy; any data obtained will be based on case reports.
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