Diagnosis and treatment of venous thromboembolism in pregnancy

Best Practice & Research Clinical Haematology Vol. 16, No. 2, pp. 279 –296, 2003 doi:10.1053/ybeha.2003.246

10 Diagnosis and treatment of venous thromboembolism in pregnancy Marc A. Rodger* MD, FRCP(C), MS c Mark Walker MD, FRCS(C) Philip S. Wells MD, FRCP(C) , MS c Departments of Medicine and Obstetrics and Gynecology, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ont., Canada

Suspected or confirmed venous thromboembolism (VTE) (deep-vein thrombosis and pulmonary embolism) in non-pregnant patients are common clinical problems with ample clinical research upon which diagnostic and treatment recommendations are based. Unfortunately, the level of complexity is increased in the diagnostic and therapeutic management of pregnancy-associated VTE by evolving physiological changes in expectant mothers, the effects of diagnostic and therapeutic management on the unborn child and the lack of validation of these management strategies in pregnancy. This chapter considers the epidemiology, pathogenesis, diagnosis and treatment of pregnancy-associated VTE. It highlights the poverty of research upon which to base clinical recommendations for this common problem yet offers practical but conservative approaches to patients with suspected and confirmed pregnancy-associated VTE. Key words: pregnancy; deep-vein thrombosis; pulmonary embolism; diagnosis and treatment.

EPIDEMIOLOGY OF PREGNANCY-ASSOCIATED VENOUS THROMBOEMBOLISM Venous thromboembolism (VTE) remains one of the most common causes of maternal mortality in the developed world.1 – 10 VTE is up to 10 times more common in pregnant women than in non-pregnant women of comparable age. Retrospective cohort studies using population-based administrative databases suggest that the incidence of VTE is 5 – 12 per 10 000 maternities in the antenatal period and 3 –7 per 10 000 maternities in the post-partum period11 – 14 in contrast to an age-and sex-adjusted incidence of 1.6 per 10 000 women and 0.2 per 10 000 women, respectively, in comparable time frames.15 These retrospective data are, however, limited by the lack of available information on the objective diagnostic tests used to establish the diagnosis (accuracy bias) and standardized diagnostic algorithms to pursue suspected events (diagnostic suspicion * Corresponding author. Address: Thrombosis Assessment and Treatment Unit, The Ottawa Hospital—General Campus, 501 Smyth Road, Ottawa, Ont., Canada K1H 8L6. Tel.: þ 1-613-798-5555 ext 12694; Fax: þ1-613-739-6102. E-mail address: [email protected] (M. A. Rodger). 1521-6926/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved.

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bias and ascertainment bias). More than a third of pregnancy-related cases of VTE occur during the post-partum period, highlighting the increased daily risk of thrombosis in the brief 6-week post-partum period compared to the 40-week antepartum period.16 The daily risk of VTE is fourfold higher in the post-partum period compared to the antepartum period.16 A recent meta-analysis demonstrated that antepartum VTE can occur in any trimester, with a higher incidence in later trimesters.16 Pregnant thrombophilic women are at an increased risk of developing VTE compared to non-thrombophilic women (3- to 15-fold higher risk).17 – 19 Higher VTE rates are also observed with advanced maternal age (over 35) and women who undergo emergency Caesarean section.20 Pregnancy-associated VTE can also lead to long-term morbidity. Eighty percent of pregnant women with VTE go on to develop post-thrombotic syndrome (leg swelling, discoloration of the skin, non-healing ulcers near the ankles and varicose veins, with the potential for breakthrough bleeding, pain, infection, or inflammation), while 65% will have objectively confirmed deep-venous insufficiency.21 Pathogenesis of pregnancy-associated venous thromboembolism Virchow’s triad identifies three initiating factors (hypercoagulability, venous stasis and vascular damage) for venous thrombosis, all three of which are normally present during pregnancy and the puerperium. Pregnancy and the puerperium are hypercoagulable states; they are associated with increased levels of procoagulant factors (increased factor V and VIII levels) and decreases in anticoagulant activity (decreased protein S levels and increased activated protein C resistance).22 Vascular damage of pelvic vessels caused by delivery (vaginally or by Caesarean section) probably contributes to postpartum venous thrombosis. Venous stasis begins by the end of the first trimester and reaches a nadir at 36 weeks as a result of increasing vein distensibility and compression of pelvic vessels by the gravid uterus23 and compression of the left iliac vein by the right iliac artery. The latter may account for the marked propensity for left leg deep-vein thrombosis in pregnancy.16 The majority (over 80%) of DVTs in pregnancy develop in the left leg.14,16 Management of suspected VTE in pregnancy One must appreciate that the literature examining the diagnostic management of suspected VTE in pregnancy is sparse. The absence of validation of diagnostic imaging procedures for suspected VTE in pregnancy and limited information about the validity of clinical assessment of suspected VTE in pregnancy make firm recommendations impossible. Furthermore, the diagnostic management of suspected VTE in pregnancy is complicated by concerns about teratogenicity and oncogenicity in the unborn child from diagnostic imaging procedures for suspected VTE. Hence, practice guidelines must be developed by extending the evidence from non-pregnant patients, considering the limited data that are available in pregnant patients and interpreting this evidence with the unique circumstances which surround pregnancy (concerns about radiation exposure to the unborn child, unique and the evolving physiology and pathophysiology of pregnancy, labor and delivery). Of significant concern to clinicians and patients is the radiation exposure to the unborn child and mother associated with diagnostic imaging used in the management of suspected VTE in pregnant women. This has been studied and reviewed by Ginsberg et al.24 This review concluded that radiation exposure in utero of up to 5 rads may

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increase the risk of childhood malignancy by up to twofold and may increase the risk of congenital eye abnormalities slightly. On the other hand the authors conclude that there appears to be no increased risk of intrauterine growth restriction, miscarriage, stillbirth or infant death. The estimated exposure to radiation of the unborn child is 0.628 rads with bilateral venography without abdominal shielding, up to 0.37 rads with pulmonary angiography by the femoral route and, in the worse case scenario, 0.58 rads with V/Q scanning.24 Maximizing efforts to limit radiation exposure using limited venography (, 0.05 rads), pulmonary angiography by the brachial route (, 0.05 rads) and low-dose perfusion scanning (omitting ventilation scanning) (, 0.012 rads) result in the unborn child being exposed to very low radiation.24 Despite the potential small absolute increased risks of exposures of the unborn child to radiation, clinicians and patients can be comforted that more good than harm can be achieved by appropriate management of suspected VTE in pregnancy when one considers the known high mortality of untreated VTE and of major bleeding with therapeutic anticoagulation in women without pulmonary embolism (PE). In contrast, spiral CT imaging in pregnant women with suspected PE is not recommended when a validated imaging procedure for suspected PE (ventilation and perfusion scanning) is available. It is estimated that spiral CT is associated with exposure of the women’s breast to radiation of 2.0 –3.5 rads.25 The delivery of 1 rad of radiation to a women’s breast increases her lifetime risk of developing breast cancer by 14%.25 The literature provides no estimate of fetal radiation exposure from spiral CT for suspected PE in a pregnant women, but given that the total radiation to expectant mothers is 2– 4 rads26 this raises the concern of fetal radiation exposure and its consequences. It has been estimated that the increased lifetime risk of malignancy from abdominal CT scanning in a 1-year old child is 0.18%.27 Furthermore, spiral CT imaging has not even yet been adequately validated in non-pregnant women with suspected PE.28,29 Given the incremental radiation exposure compared to V/Q scan, only if spiral CT is established as a better diagnostic tool for suspected PE in non-pregnant patients should it be studied in pregnancy. The following discussion reviews the management of suspected PE and DVT in pregnancy by considering evidence in non-pregnant patients and the limited evidence in pregnant patients and suggests practical (and relatively safe) diagnostic management approaches (that nonetheless require further validation). Management of suspected pulmonary embolism in pregnancy Pulmonary embolism (PE) is an important diagnosis to establish or refute. In nonpregnant patients, undiagnosed PE has a hospital mortality rate as high as 30%—which falls to near 8% if diagnosed and treated appropriately.30 – 32 However, the mortality is less than 2% in ambulatory patients.33 Pregnant women with suspected PE generally have less concomitant morbidity (e.g. cardiopulmonary disease) than unselected populations with suspected PE. The diagnosis of pulmonary embolism remains one of the most difficult problems confronting clinicians caring for pregnant women. Pulmonary embolism is considered in the differential diagnosis of many clinical presentations, including chest pain, dyspnoea, hemoptysis and unexplained tachycardia. Such symptoms are common in pregnant women and hence the diagnosis is frequently considered. In recent studies in non-pregnant patients less than 15 –35% of patients suspected of having PE actually have PE.33 – 35 In pregnant patients the prevalence of disease in those suspected of PE appears to be even lower than in non-pregnant patients, providing some reassurance to clinicians and patients. In one small retrospective cohort study examining ventilation perfusion scanning for suspected PE

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in pregnant women, only 1.8% had high-probability V/Q scans and less than 6% were treated for VTE after the completion of diagnostic imaging.36 This suggests that many patients without PE are needlessly hospitalized, anticoagulated and some transferred to larger centers for confirmatory testing. However, given the high mortality of untreated pulmonary embolism, timely diagnostic testing must be performed to enable the initiation of antithrombotic therapy for patients proven to have this condition while avoiding the risks of anticoagulation for patients in whom this diagnosis is excluded. The clinical assessment for pulmonary embolism will be considered first by examining the diagnostic value of the individual components (i.e. symptoms, signs, risk factors, laboratory tests, electrocardiogram, arterial blood gas and chest X-ray) and then considering the diagnostic value of the overall clinical assessment (i.e. the clinician’s overall diagnostic impression). Research on the clinical assessment of suspected pulmonary embolism in pregnant patients is very limited. This review will focus mainly on data in non-pregnant patients that we believe may be cautiously extended to pregnant patients. Four authors have reported on the sensitivity and specificity of individual signs and symptoms.37 – 40 The patient’s age is consistently a statistically significant univariate predictor for pulmonary embolism across these studies. This is consistent with population-based epidemiological data demonstrating an increased incidence of PE with age.15 In post-partum women, higher VTE rates are observed with advanced maternal age (over 35).20 Overall, however, individual presenting symptoms do not reliably differentiate between patients with and without pulmonary embolism. Patients with PE are more likely to be tachypnoeic and tachycardic than patients without PE but these differences were only statistically significantly different in one study. In studies reported to date there appears to be no difference in blood pressures, the presence of a pleural rub on auscultation or temperatures in patients with confirmed and suspected PE. One commonly held misconception is that the presence of chest wall tenderness in patients with pleuritic chest pain excludes pulmonary embolism.41 The presence of a fourth heart sound (S4), loud second pulmonary heart sound (P2), and inspiratory crackles on chest auscultation were more common in patients with pulmonary embolism than in patients without pulmonary embolism in one study.37 Risk factors for venous thromboembolic disease are well characterized in the literature.42,43 In a review of 1231 non-pregnant patients treated for confirmed venous thromboembolic disease, one or more risk factors was present in over 96% of the patients. Furthermore, in the PIOPED study, the presence of one or more risk factors was more common in patients with, as opposed to without, PE.34 In unselected patients with suspected PE, the only risk factors which are consistently present more often in patients who are ultimately confirmed to have PE are immobilization, recent surgery, malignancy and previous venous thromboembolic disease.37 – 40 However, only immobilization and recent surgery reached statistical significance. Risk factors that have been explored specifically in pregnancy include prolonged bed rest, maternal age, family history of thrombosis, parity, previous thrombosis, thrombophilia, previous superficial phlebitis, pre-eclampsia, tobacco use and operative delivery (Caesarean section). In an adequately powered case-control study prolonged bed rest during pregnancy was not demonstrated to be a risk factor for VTE.44 In a small case –control study, family history of thrombosis (first-degree relatives) was demonstrated to be a risk factor for pregnancy-associated VTE.45 In a large populationbased retrospective cohort study of pregnant women, Caesarean section, parity greater than three, pre-eclampsia and tobacco consumption were demonstrated to be risk factors for pregnancy-associated VTE while maternal age was not an independent

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risk factor. However, in another retrospective cohort study higher VTE rates were observed with advanced maternal age (over 35).20 Women with pregnancy-associated VTE are more likely to have FVL or PTG than pregnant controls without VTE.17,18 Recent studies have demonstrated that the expected antepartum VTE rates in thrombophilic women with prior idiopathic VTE are 10% (95% confidence intervals 0.25 – 44.5%).46 Thrombophilic women with prior secondary proximal VTE are estimated to have a 6% (95% confidence intervals 0.17 – 31.9%) risk of antepartum VTE recurrence in subsequent pregnancies.46 Superficial venous thrombosis has also been shown to be an independent risk factor for VTE in pregnancy (odds ratio of 9.4)16 in case– control studies.47 A variety of electrocardiogram (ECG) changes have been suggested to have diagnostic value in non-pregnant patients with suspected PE.48 – 51 However, the majority of these investigations have studied only patients with confirmed PE. Few authors have reported on the prevalence of ECG changes in patients with suspected PE. The diagnostic value of a test can be determined only by applying the test in patients with suspected disease and then determining whether the test is predictive of outcome. Further, previous investigations examining the diagnostic value of the ECG in suspected pulmonary embolism have been limited by patient selection (critical care patients only)52,53 or by not comparing the diagnostic value of the ECG to an appropriate reference standard (perfusion scans only).53 In a study of unselected patients with suspected PE with gold standard outcome measures we found that only tachycardia and incomplete right bundle branch block were significantly more frequent in PE patients than no PE patients, however, these ECG changes were only marginally more frequently observed in PE patients or rarely observed thus limiting their diagnostic utility.54 Another misconception is that a normal A-a gradient excludes PE55 despite reports to the contrary.56 Two authors have proposed prediction rules based on arterial blood gas but these rules could not be validated in subsequent studies.56 – 58 Recently, Egermayer et al showed that a negative D-dimer, a PaO2 . 80 mmHg and a respiratory rate less than 20, also had a negative predictive value of 100% in patients with suspected PE. In our study population we were able to demonstrate a negative predictive value of only 95% with this rule.58,59 In summary, ABGs should not be ordered to rule in or rule out pulmonary embolism in non-pregnant patients. In PIOPED, the most sensitive chest X-ray change was atelectasis or parenchymal abnormality and had a sensitivity of only 68%.49 In another investigation, chest X-rays in patients with suspected PE were interpreted by radiologists who agreed on the presence of pulmonary embolism in only one-third of patients; in only one-third of these patients was the diagnosis correct.60 In summary, individual potential clinical predictors of PE in pregnant women with suspected PE have not been adequately studied. However, by extension from good studies in unselected patients with suspected PE, while some individual findings on history, physical examination, ABG, ECG and CXR have some discriminatory ability they are not of sufficient diagnostic value to exclude PE or diagnose PE. Despite the limitations of the individual clinical predictors described above, in the early 1990s the PIOPED investigators demonstrated that, indeed, the overall clinical assessment (i.e. the clinician’s overall diagnostic impression) was of utility in diagnostic management. In the PIOPED study, experienced clinicians were able to separate a cohort of patients with suspected pulmonary embolism into high-, moderate- and lowprobability groups using clinical assessment alone.61 More recently, Perrier and colleagues were also able to stratify patients into different risk categories using clinical assessment alone.62 In both of these studies, patients were stratified into risk

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categories using the clinical judgment of the individual clinicians based on overall diagnostic impression alone (i.e. not using a pre-defined clinical decision tool). Once again, while the diagnostic value of a clinician’s overall diagnostic impression has not been specifically studied in pregnant women with suspected PE we are cautiously optimistic that this can be used in the management of pregnant women with suspected PE. Several investigators have recently published experience with explicit clinical models for determining the pre-test probability of pulmonary embolism.63 – 65 The studies developing and validating these clinical models excluded pregnant women. Further investigation will be required to either validate these clinical models in pregnant women or to develop clinical models for pregnant women. Given the preponderance for left-leg DVTand a different distribution of VTE risk factors it is likely that a specific clinical model to assign pre-test probability for pulmonary embolism in pregnancy will be required. For over 30 years ventilation perfusion (V/Q) lung scanning has been used as the imaging procedure of choice for the evaluation of patients with suspected pulmonary embolism. The accuracy of lung scanning has been evaluated in two studies that used pulmonary angiography as the gold standard.61,66 These studies demonstrated that a normal perfusion lung scan essentially excludes the diagnosis of pulmonary embolism, and a high probability lung scan has an 85 – 90% positive predictive value for pulmonary embolism. However, using pulmonary angiography as the gold standard, two studies have demonstrated that between 45 and 66% of high-probability lung scans are falsely positive when a skilled clinician deemed the patients’ pre-test probability for pulmonary embolism was low.61,66 Similarly, if the clinical pre-test probability is high but the scan non-diagnostic, further investigation—preferably angiography—is necessary to exclude or confirm the diagnosis of pulmonary embolism. A limitation of ventilation perfusion lung scanning in the non-pregnant population is that most lung scans fit into a nondiagnostic category (neither normal nor high probability) in which the incidence of pulmonary embolism varies from 10 to 30%. In pregnant women a greater proportion of normal scans are seen (over 70%), probably due to less concomitant respiratory disease than in other patient populations with suspected PE.36 Criteria have been developed by the PIOPED investigators to distinguish moderate-probability (termed intermediate, incidence of pulmonary embolism 30%) from lower-probability (termed low, incidence of pulmonary embolism 15%) scans. However, the designation of a lowprobability lung scan has been criticized because of the interpretation by some clinicians that ‘low probability’ means ‘no probability’ and on this basis anticoagulant therapy has been withheld inappropriately in some patients with serious consequences.67,68 Therefore we prefer to use the designation of non-diagnostic for all scan results that are neither normal nor high probability. In pregnant women with suspected PE, fewer patients will have non-diagnostic scans (25%) than in unselected patients.36 Further testing is required to exclude the diagnosis of pulmonary embolism in these patients. The presence or absence of an intravascular filling defect on pulmonary angiography, respectively, confirms PE or refutes PE.61 Despite remaining the gold standard test for pulmonary embolism, many clinicians choose not to pursue pulmonary angiography in patients with suspected PE.69 – 72 The reasons why clinicians do not use the gold standard include (1) a fear of the mortality associated with pulmonary angiography, (2) its limited availability after hours and in smaller centers, and (3) the expense and expertise required to perform pulmonary angiography. Although the procedure is usually well tolerated, arrhythmia and hypotension, as well as other adverse reactions to contrast dye, may be observed. The best data on morbidity and mortality, death in 0.5% and major non-fatal morbidity in 1.0%, were determined prior to the widespread

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use of non-ionic low-osmolar contrast.73 Further, 3/5 of deaths were in patients with poor cardiopulmonary reserve prior to angiography so that the procedure is probably safer in patients without poor cardiopulmonary reserve. A more recent singleinstitution study had no fatalities in 1400 patients and major complications in 0.3%.74 Regardless, the above limitations are probably the reasons why a significant number of patients with non-diagnostic V/Q scans are managed inappropriately.69 Further, pulmonary angiography is also an imperfect test. A patient with a normal pulmonary angiogram can expect a 2.2% (95% CI of 0.3 –8.0%) venous thromboembolic event rate at 1 year follow-up.66 Thus, although we are not suggesting that performing angiography in patients with suspected pulmonary embolism is an incorrect approach the limitations must be appreciated. The greatest utility for venous ultrasound imaging in non-pregnant patients with suspected pulmonary embolism is in patients with (1) high pre-test probability for pulmonary embolism and (2) risk factors for pulmonary embolism and signs and symptoms of DVT. In these two groups ultrasound will be positive in 46 and 15%, respectively.75,76 This eliminates the need for pulmonary angiography in many patients with these characteristics. We have demonstrated that, in non-pregnant patients with non-high probability VQ scans and initial normal ultrasonography, the performance of three additional venous ultrasound imaging tests over a 2-week period (serial ultrasound testing), can be used safely to exclude the diagnosis of pulmonary embolism.77 The limitations of this approach are that it is both inconvenient and costineffective became relatively few patients undergoing serial testing will actually have pulmonary embolism. In a retrospective study of women investigated for suspected PE, bilateral venous ultrasound imaging or impedance plethysmography was performed in 67/113 pregnant patients and was negative in all patients. Serial imaging was performed in seven patients and all results were normal. Prior to concluding that imaging for DVT is not fruitful in pregnant patients with suspected PE, larger studies are required to validate the low incidence of concomitant PE and positive venous ultrasound imaging for DVT in pregnant women with suspected PE. D-Dimer is a degradation product of a cross-linked fibrin blood clot. Levels of Ddimer are typically elevated in patients with acute VTE. D-dimer levels may also be increased in a variety of non-thrombotic disorders, including recent major surgery, hemorrhage, trauma, malignancy or sepsis, and they increase throughout normal pregnancy.78 Near term, and in the post-partum period, most normal pregnant women will have abnormal D-dimer levels.78 Therefore, D-dimer assays are, in general and more so in pregnancy, sensitive but non-specific markers for VTE. Many different Ddimer assays have been evaluated for the diagnosis of VTE in non-pregnant women and the accuracy of these tests varies. The most sensitive D-dimer tests are the enzymelinked immunosorbent assays (ELISAs). Two other D-dimer assay methods that have been evaluated as diagnostic markers for pulmonary embolism are a whole-blood agglutination assay (SimpliRED) and latex agglutination plasma assays.79 These assays have the advantages that they are simple to perform, have a rapid turn-around time and are inexpensive. They are less sensitive but more specific than the ELISA assay. No Ddimer test has 100% sensitivity, so that D-dimers should not be used alone to exclude DVT. To conclude, we suggest that women with suspected PE in pregnancy should have a pre-test probability assigned on the basis of clinical assessment and D-dimer. All women with suspected PE should undergo diagnostic imaging (Figure 1). Those with leg symptomatology suggestive of DVT should first have venous ultrasound imaging and, if a proximal DVT is found, should be treated with therapeutic anticoagulation. In

No leg symptoms

Leg symptoms CUS Noncompressible segment on CUS

Normal

Perfusion scan

Abnormal

Normal

Ventilation scan

High probability

Non-diagnostic All others

D-dimer –‘ve and low PTP

Pulmonary angiography

Filling defect Excludes PE

Confirms PE

Serial CUS until day 14

Normal

Normal

Excludes PE

Noncompressibility Confirms DVT

Figure. 1. Algorithm for suspected PE in pregnant women. PE, pulmonary embolism; CUS, venous compression ultrasound imaging; PTP, pre-test probability; DVT, deep-vein thrombosis.

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Pregnant women with suspected PE

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those without leg symptomatology suggestive of DVT, or in those with leg symptomatology suggestive of DVT who have negative venous ultrasound imaging, lung scintigraphy should be performed. Perfusion scans should be performed first and, if normal, PE is excluded. If the perfusion scan is abnormal then ventilation scans should be performed. Patients with high-probability scans should be treated for PE. Patients with non-diagnostic scans and low pre-test probability and negative D-dimers should have serial venous ultrasound imaging and should be considered PE-negative if ultrasounds remain negative to day 14. In all other patients with nondiagnostic scans (that is, those with positive D-dimers or moderate to high pre-test probability) pulmonary angiography by the brachial route should be performed. While this approach needs to be validated in a well-designed management study we believe that it is very probably a safe and practical diagnostic approach to this common medical problem in pregnancy.

Practice points † nuclear medicine imaging is the test of choice for suspected pregnancyassociated PE † pregnant women with suspected PE who have leg symptoms or signs of DVT should have venous ultrasound imaging first (prior to nuclear medicine imaging) † a normal V/Q scan excludes PE † pregnant women with indeterminate scans should have venous ultrasound imaging of the leg and, if normal, should have pulmonary angiography (except those with low pre-test probability and negative D-dimers where serial venous ultrasound imaging is probably safe) † a high-probability scan confirms PE

Research agenda † clinical assessment, D-dimer testing, nuclear medicine imaging and combinations of the former need to be validated in diagnostic management strategies in pregnant women with suspected PE

Management of suspected DVT in pregnancy Deep-vein thrombosis can present with leg discomfort (calf, thigh or buttock), leg swelling, pitting edema, discoloration (redness or cyanosis) and warmth. Leg swelling is a common complaint or finding in pregnancy so DVT is a frequently considered diagnosis. As is the case with pulmonary embolism, while no specific feature of the history or physical examination can be used to diagnose DVT or refute a diagnosis of DVT, clinical assessment of non-pregnant patients has been demonstrated to be useful in classifying patients into low, moderate and high pre-test probabilities.80,81 However, once again, these studies did not focus on the sub-group of pregnant patients. It is very likely that the distribution of physical findings (e.g. left leg swelling) and risk factors (e.g. trauma, immobilization, surgery, malignancy) would be different in pregnant women. The performance of clinical assessment (with or without explicit clinical models) may differ in this sub-population.

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Venograms are the gold standard for the diagnosis of DVT. However, venograpy is uncomfortable (involves needle puncture of vein on the dorsum of the foot), invasive, associated with anaphylaxis or renal failure from exposure to contrast dye (albeit rare with low ionic contrast media) and, as discussed above, is associated with exposure of the unborn child to radiation. As a consequence, clinicians and patients are reluctant to use venography to investigate suspected DVT in pregnancy. In the non-pregnant population the diagnostic imaging procedure of choice has become venous ultrasound imaging. Venous ultrasound imaging is non-invasive and is not associated with exposure of unborn child to radiation. Serial venous ultrasound imaging has been validated in clinical management studies to exclude DVT safely in unselected patients and to have high sensitivity and specificity for proximal DVT in accuracy studies in non-pregnant populations.82 Impedance plethysmography (IPG) is also a non-invasive test and has been investigated in the diagnostic management of suspected DVT. In fact, IPG is the only non-invasive test for VTE that has been validated in pregnancy.83 However, IPG has been shown to be less sensitive and specific than compression ultrasound in non-pregnant patients and is no longer widely available.84 Studies are required to validate venous ultrasound imaging in pregnancy. Venous stasis increases throughout pregnancy secondary to increases in vein diameter and compression from the gravid uterus.23 These physiological changes in pregnancy may affect the diagnostic accuracy of venous ultrasound imaging in pregnant women. While ongoing studies will help to clarify the validity of diagnostic approaches to suspected DVT in pregnancy we suggest the following (Figure 2). Women with suspected DVT should be assigned a pre-test probability and have D-dimer testing performed. All pregnant women with suspected DVT should have venous ultrasound imaging. If a proximal DVT is detected then treatment should be initiated. In women with high pre-test probability and positive D-dimer and a normal initial ultrasound, venography should be considered. All other women should undergo serial compression ultrasound imaging for 14 days. If a proximal DVT is detected then treatment should be initiated. If no DVT is detected by day 14 then DVT can be considered excluded.

Practice points † DVT is confirmed if venous ultrasound imaging demonstrates a noncompressible segment in a proximal leg vein † if the pre-test probability is high and D-dimer positive, venography should be performed if the initial venous ultrasound imaging is negative † a single venous ultrasound should not be used to exclude DVT in pregnancy. Serial ultrasounds (every 3 –14 days) are recommended to exclude pregnancyassociated DVT

Research agenda † clinical assessment, D-dimer testing, leg venous ultrasound imaging and combinations of the former need to be validated in diagnostic management strategies in pregnant women with suspected DVT

Pregnant woman with suspected DVT

D-dimer PTP CUS

D-dimer +’ ve and High PTP

Non-compressible segment on CUS

All others

Normal CUS

Serial CUS until day 14

Venography

Confirms DVT

Normal

Normal

Excludes DVT

Non-compressibility

Confirms DVT

Figure. 2. Algorithm for suspected DVT in pregnant women. DVT, deep-vein thrombosis; PTP, pre-test probability; CUS, venous compression ultrasound imaging.

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Filling defect

Non-compressible segment on CUS

Normal CUS

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TREATMENT OF VTE IN PREGNANCY The absence of randomized controlled trials in pregnancy complicates VTE treatment recommendations in pregnancy. VTE treatment recommendations are further complicated by the ongoing increased risk of VTE from pregnancy, the need for reversal of anticoagulation at the time of delivery and the effects of anticoagulants on the unborn child. These factors lead to the need for individualized treatment recommendations that should be made in conjunction with a hematologist specializing in the care of venous thromboembolic disease. In making treatment recommendations evidence must be borrowed from VTE treatment outside pregnancy and tailored to pregnancy. The initial management of confirmed VTE in pregnancy necessitates immediate anticoagulation with unfractionated heparin or low-molecular-weight heparin (LMWH). Administration LMWH has become an increasingly desirable alternative to conventional unfractionated heparin (UFH) therapy in the treatment of VTE in non-pregnant patients. A longer plasma half-life, and an almost complete bioavailability, permit LMWH to be administered subcutaneously once or twice daily, without the necessity of laboratory monitoring and dose adjustments.85 However, long-term use in pregnancy is more complex than short-term use in the non-pregnant population. The pharmacokinetics of low-molecular-weight heparin in pregnancy are poorly understood but studies clearly show that drug clearance is dependent on gestational age.86,87 Other studies have also suggested that prolonged use may result in an accumulation of dose effect.88 Hence, treatment with full-dose LMWH in pregnancy may best be accomplished with monitoring of drug effect with target anti-Xa levels of 0.5 – 1.1 3 to 6 hours post-dose. We do weekly anti-Xa monitoring in patients on full-treatmentdose LMWH. Several meta-analyses of randomized controlled trials demonstrate that LMWH is at least as safe and effective as UFH in the treatment of acute VTE.89,90 The only randomized controlled trial comparing LMWH to unfractionated heparin in the treatment of pregnancy-associated VTE was only adequately powered to determine difference in bone mineral density. In this study LMWH was found to cause less bone loss than heparin.91 No adequately powered pregnancy studies examining differences in efficacy and other safety parameters have been published, however, this study and a small series suggest equivalence.92 Outpatient-based LMWH therapy has been shown to be feasible, safe and effective in unselected patients.93 LMWH is, however, associated with serious side-effects (hemorrhage94, osteoporosis/fractures87 and heparin-induced thrombocytopenia95 that can be fatal96) and LMWH may limit peripartum analgesic options because of the risk of epidural hematoma.97 LMWH does not cross the placenta, and in a recent systematic review of LMWH use in pregnancy the authors concluded that the use of LMWH is safe for the mother and fetus.98 LMWH is only minimally secreted into the breast milk and can be safely given to nursing mothers.99 LMWH should be avoided in renal failure and in situations where urgent reversal of anticoagulation may be required (e.g. high bleeding risk or imminent surgery). In these situations intravenous unfractionated heparin is recommended. Warfarin should be avoided in pregnancy as it is associated with congenital malformations (especially with exposure from 6 to 12 weeks) and fetal and neonatal hemorrhage.100 Recognizing the above considerations, our practice is to treat acute VTE in pregnancy with full-dose LMWH for 3 weeks and then reduce the dose to half of the full treatment dose throughout the remainder of pregnancy and at least throughout the post-partum period. We feel comfortable reducing the dose to half-treatment dose

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given evidence that prophylactic-dose LMWH (dalteparin 5000 units per day) has been shown to have efficacy and safety as comparable to that of oral anticoagulant therapy (INR 2-3) in the longer-term therapy (secondary prevention) for acute DVT.101 A higher dose appears justified given the ongoing hypercoagulability of the pregnant state. A halftreatment dose permits ongoing therapy without the need for laboratory monitoring of drug effect. Platelet monitoring is necessary to exclude HIT (we do a weekly platelet count for a month then monthly counts until term). A minimum of 3 months of anticoagulation is recommended. Three months is probably adequate for secondary VTE (i.e. VTE due to plaster casts, immobilization greater than 72 hours, major surgery) in the antepartum period and any VTE in the post-partum period. Longer anticoagulation (e.g. 6 months or greater) should be considered for idiopathic VTE occurring during the antepartum period. If the VTE is diagnosed near term (over 37 weeks) then consideration should be given to placement of an IVC filter (preferably retrievable) and a planned induction after reversal of anticoagulation. Reversal of anticoagulation without IVC filter protection is strongly discouraged in the 4-week period after the diagnosis of the VTE given the mortality of untreated thromboembolism in this period.102 Longer unanticoagulated periods can be considered if the VTE is more remote.102 Practice points † LMWH or standard heparin therapy should begin immediately if DVT or PE is suspected and if confirmed. If timely diagnostic imaging is available therapy can be withheld † LMWH should be used in the secondary prevention of pregnancy-associated VTE † warfarin should be avoided in pregnancy † a minimum of 3 months of anticoagulation is required. Anticoagulation should be continued throughout pregnancy and the post-partum period. Anticoagulation for 6 months or longer is recommended for idiopathic VTE (idiopathic VTE includes pregnancy-associated VTE in the antepartum period) † anticoagulation should not be interrupted without IVC filter protection in the first 4 weeks after VTE diagnosis

Research agenda † randomized controlled trials are required to validate all VTE treatment approaches in pregnancy

SUMMARY Clinicians and patients are hampered by the lack of specific evidence to guide the management of suspected and confirmed VTE in pregnancy. Further research is required to make confident recommendations in this area. Nevertheless, these are common problems in pregnancy so evidence must be borrowed from non-pregnant populations and individualized diagnostic and treatment approaches applied to these patients.

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ACKNOWLEDGEMENTS Dr M.A. Rodger is the recipient of the Heart and Stroke Foundation of Canada’s Dr. Mavreen Andrew New Investigator Award. Dr M.C. Walker is the recipient of a Career Scientist Award from the Ministry of Health of Ontario. Dr Wells is a Canada Research Chair in Thromboembolic Diseases.

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