REVIEW URRENT C OPINION
Pregnancy and venous thromboembolism Eleonora Ralli a, Luigi Zezza b, and Donatella Caserta a
Purpose of review This review provides a concise and complete overview of diagnostic work-up and treatment of venous thromboembolism in pregnancy, with attention to recent research developments and recent applicable guidelines. This may be useful for all the players of the multidisciplinary interaction needed in this disease management, namely cardiologists and gynecological/obstetric teams. Recent findings Venous thromboembolism is, in the developed world, a major cause of maternal morbidity and mortality during pregnancy or early after delivery, with a reported incidence ranging from 0.49 to 2.0 events per 1000 deliveries. It is a particularly challenging issue and there is no common consensus on the major themes of this condition. Diagnostic options, prophylaxis and management, in the antenatal, childbirth and postnatal periods, are carefully analyzed in the light of the most recent published data. Besides, old and recent knowledge must be seen through the clinician’s skilled and watchful eyes, deciding on a case-tocase and actively contributing in reducing pregnancy-related morbidity. Summary Although there is an ongoing debate on various aspects of this condition and there is a paucity of highquality studies, this review attempts to simplify the complex aspects of joining safety and efficacy in diagnosing and treating a possible two-people life-threatening disease. Keywords pregnancy, thromboprophylaxis, venous thromboembolism
INTRODUCTION Venous thromboembolism (VTE) is, in developed countries, a major cause of maternal morbidity and mortality during pregnancy and postpartum, with a reported incidence ranging from 1 to 2 events per 1000 deliveries. This article briefly reviews the areas of controversy and provides recommendations for the treatment and prophylaxis of VTE in pregnant patients. Strong evidence for the management of pregnancy-related VTE is still missing, mostly because pregnant women have been excluded from all major trials investigating different diagnostic tools and treatment regimens. Nevertheless, proper evaluation of the involved risk factors is mandatory to reduce the incidence of pregnancy-related VTE and to improve outcomes. With regard to future research, large-scale randomized trials of currently used interventions should be conducted.
EPIDEMIOLOGY AND RISK FACTORS VTE is a condition in which the blood clots inappropriately. The term VTE encompasses a continuum, including both deep vein thrombosis (DVT) and pulmonary embolism [1]. VTE episodes are four to five-fold higher [2,3] during pregnancy than in a
nonpregnant status at the same age, and it is the leading cause of maternal mortality in the developed world. An even 20-fold to 80-fold higher VTE risk has been reported within the first 6 weeks following delivery [2,4,5]. The overall incidence of thromboembolic events in pregnancy is about 1 to 2 per 1000 deliveries [2,6–8]. About 80% of pregnancy-associated VTE episodes is represented by isolated DVT and about 20% of them by pulmonary embolism [2]. Normal pregnancy is known to be associated with a hypercoagulable state characterized by increased concentrations of some procoagulant factors (e.g., factors VII, VIII, X, von Willebrand factor and fibrinogen) and by a simultaneous
a
Department of Obstetrics, Gynecological and Urological Sciences and Unit of Cardiology, Clinical and Molecular Medicine Department, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy b
Correspondence to Eleonora Ralli, MD, Department of Obstetrics, Gynecological and Urological Sciences, Sant’Andrea Hospital, Sapienza University of Rome, via di Grottarossa 1035–1039, 00189, Rome, Italy. Tel: +39 063 377 5696; fax: +39 063 377 6660; e-mail: eleonora. [email protected], [email protected], [email protected] Curr Opin Obstet Gynecol 2014, 26:469–475 DOI:10.1097/GCO.0000000000000115
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KEY POINTS VTE is, in industrialized countries, a major cause of maternal morbidity and mortality during pregnancy or early after delivery.
pregnancy. Clinical decision rules using typical signs and symptoms (leg swelling, tachycardia, tachypnea and dyspnea) have never been validated in pregnant patients. The cornerstone of diagnosing pregnancy VTE is the demonstration of presence of the clot [26 ]. D-dimer testing is not currently included in several diagnostic algorithms of suspected pulmonary embolism in both pregnancy and early postpartum period [27,28]; it is considered only in the work-up of suspected iliac DVT diagnosis, when positive in the presence of negative leg compression ultrasound, a condition in which MRI of the pelvic vessels is advised [27,29]. However, in the presence of a considerably high D-dimer value, the first further recommended diagnostic step is a venous Doppler ultrasound of the lower limbs. If positive, diagnosis can be considered completed as the treatment for both clinical entities (DVT and pulmonary embolism) is similar, and radiological second level examinations, involving a radiological risk, appear to be not acceptable to both the fetus and the mother [30]. In case of a negative Doppler examination, additional diagnostic tests must be performed, which should be different in pregnant women as compared with those normally used in the general population. A debate also exists with regard to the diagnostic value of lower limb venous echo color Doppler. Chest X-ray remains crucial for the next diagnostic path, allowing clinicians to choose either between computed tomography (CT) angiography and lung perfusion scintigraphy, when normal, or suggesting the choice of combined ventilation/perfusion scan scintigraphy, when abnormal. With regard to the ideal diagnostic path to be followed, published data remain, however, inconsistent and contradictory, as studies comparing the two diagnostic techniques are characterized by an extremely low sample size [31]. Considering the comparable diagnostic accuracy of the two imaging modalities [31], the choice is often guided by a careful multidisciplinary clinical evaluation. Patients with history of renal failure or of contrast allergy certainly avail themselves of the use of pulmonary scintigraphy. Furthermore, considering the increased exposure of breast tissue following the use of angio-CT, lung perfusion scintigraphy is to be preferred in patients with normal radiographic examination and with low probability of presence of additional lung diseases [31,32]. The risks arising from exposure to ionizing radiation may be avoided when MRI is considered for diagnostic purposes. However, this technique has a largely inferior diagnostic accuracy compared with angio-CT and scintigraphy [33] and requires use of gadolinium, which has not yet been adequately studied in pregnancy as to possible fetal damage, although it has been &
A multidisciplinary approach is needed in this disease management (cardiologists and obstetrics/ gynecologists). Diagnosis, prophylaxis and management, of this condition is particularly challenging. There is no common consensus on the major themes of this disease.
decrease of other anticoagulant factors, such as protein C and protein S [9]. When DVT occurs during pregnancy, it is more likely to be proximal, massive [10] and in the left lower extremity [11]. Apart from hypercoagulability, other pregnancyrelated physiological changes become key factors for development of VTE, such as an increased venous capacitance, a decreased venous outflow [12,13], vein mechanical obstruction due to the uterus [14], decreased mobility [15–17] and increased vascular injury [3,7]. Of note, the most important risk factor for development of VTE in pregnancy is represented by a history of thromboembolic events. Recurrent VTE represents about onethird of VTE events in pregnancy [18]. An additional VTE risk factor, able to complete the recognition of women with excessive VTE hazard, is congenital or acquired thrombophilia. The risk of a thromboembolic event occurring during pregnancy has been shown to differ according to the nature of the thrombophilia, varying from 5 to 33% [4]. Among patient characteristics, predictors of VTE have been recognized in multiparity [19], AfroAmerican race [20] and age more than 35 years [3,19,20]. There is also a strong association between cigarette smoking and an increased VTE risk in pregnancy [21–23]. The use of assisted reproductive technologies [24], or the presence of gestational diabetes, preeclampsia [3,21–23], transfusions [23], infections during the postpartum period [11] and bleeding in pre and postpartum periods [21,23,24] have been described as complications of pregnancy and childbirth associated with an increased VTE risk. Furthermore, caesarean section is associated with an increased VTE risk, especially in the emerging setting [25].
DIAGNOSTIC CHANCES The use of diagnostic algorithms for VTE in nonpregnant patients is not adequate when applied in 470
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sporadically used for the diagnosis of placenta accreta and leiomyoma without reported harmful fetal effects [34]. The recent introduction of realtime MRI, using ‘fast imaging with steady-state precession’, not susceptible to motion artifacts and not requiring gadolinium, has been able to provide promising results with high sensitivity (85%) and specificity (98%) in nonpregnant patients [34] and in few diagnostic trials of pulmonary embolism in pregnancy, even if it still requires adequate validation.
MANAGEMENT There is currently broad agreement, as shown in a recent review by Okoroh et al. [35], that women should be assessed for VTE risk preconception and again during pregnancy in order to guide VTE thromboprophylaxis. Inconsistencies in international guidelines include advice regarding which group of women to offer thromboprophylaxis to, and which options should be offered to pregnant women and the duration of prophylaxis also vary. Women who have had a previous episode of VTE may, for example, be recommended long-term antenatal prophylaxis as well as prolonged postnatal prophylaxis, whereas women undergoing caesarean section may, for example, only be recommended postnatal prophylaxis for a few days. Options for VTE thromboprophylaxis include both pharmacologic agents and nonpharmacologic methods. Pharmacologic agents that have been used include the following: unfractionated heparin (UFH) or low molecular weight heparin (LMWH), aspirin, a platelet aggregation inhibitor, warfarin, a vitamin K antagonist, hydroxyethyl starch, a nonionic starch derivative, fondaparinux, a selective inhibitor of activated factor X and danaparoid, a heparinoid. Mechanical methods that have been used include the following: graduated compression stockings, intermittent pneumatic compression, venous foot pumps, early mobilization and surveillance [36,37].
MANAGEMENT DURING PREGNANCY: LOW MOLECULAR WEIGHT HEPARIN AND UNFRACTIONATED HEPARIN AT COMPARISON The most indicated drugs for treatment and VTE prevention in pregnancy are heparins [38 ]. Both forms, UFH and LMWH, are unable to cross the placental barrier and they are not secreted in breast milk in significant amounts [38 ]. LMWH is generally used for prophylaxis. It is still unknown if dose, adjusted by weight, renal function and therapeutic target, requires further correction in pregnant women. Some experts argue the need to monitor periodically, about every &
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1–3 months, the anti-Xa activity levels, 4–6 h after injection, and adjust dose in order to maintain the levels of anti-Xa activity in the range of 0.6–1.0 IU/ml. Among the potential advantages, the most important is a lower rate of bleeding [39]. Moreover, LMWH administration has been shown to be associated with a lower risk of heparininduced thrombocytopenia [40], less harmful bone tissue effect [41] and lower allergic response risk. The only disadvantage is the long half-life that can lead to childbirth complications. Four possible dosages are recommended by American College of Chest Physicians guidelines, graded across the levels of both thrombotic and hemorrhagic risks. The first and lower is the prophylactic LMWH dose, represented by enoxaparin 4000 IU or dalteparin 5000 IU or tinzaparin 4500 IU or nadroparin 2850 IU subcutaneously every 24 h (at extremes of body weight, modification of dose may be required). The second advised dosage is the intermediate-dose LMWH, consisting in enoxaparin 4000 IU or dalteparin 5000 IU subcutaneously every 12 h possibly used in prophylaxis of conditions at higher thrombotic risk. The third and fourth advised dosages are those of adjusted-dose LMWH, represented by a weight-adjusted or a full-treatment dose of LMWH, respectively, administered once daily or b.i.d. and consisting in enoxaparin 1 mg/kg every 12 h or dalteparin 100 U/kg every 12 h or dalteparin 200 U/kg once daily or tinzaparin 175 U/kg once daily [42] (Fig. 1). UFH is used mainly for therapeutic purposes; intravenous (i.v.) UFH administration in the form of sodium heparin is recommended at adequately weight-corrected doses of 80 IU/kg in bolus i.v. and 18 IU/kg/h continous i.v. administration, titrated to a target activated partial thromboplastin time (aPTT) of 1.5–2 [42] (Fig. 1). In particular, in the acute treatment of VTE happening in proximity of operative or vaginal delivery, UFH use appears to be preferred to that of LMWH. Its subcutaneous form, namely calcium heparin, has proven less effective and its effect less predictable in relation to dose.
MANAGEMENT OF LABOR AND DELIVERY In women treated with LMWH, this drug should be replaced with UFH in the last month of pregnancy or as soon as possible, if delivery is imminent [43]. Moreover, delivery should be planned and the time during which anticoagulant therapy is stopped around the time of labor should be minimized [44]. For vaginal delivery, the need of UFH, a drug with shorter half-life, complies not only with the aim of reducing bleeding risk during childbirth but, more importantly, with that of minimizing the risk of epidural hematoma at the spinal site during
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Venous thromboembolism in pregnancy
Low-dose anticoagulation
Prophylaxis
Treatment
LMWH
UFH
Intermediate anticoagulation
s.c. every 24 h: Enoxaparin 4000 IU Dalteparin 5000 IU Tinzaparin 4500 IU Nadroparin 2850 IU
s.c. every 12 h: Enoxaparin 4000 IU Dalteparin 5000 IU
Full-dose anticoagulation
80 IU/kg in bolus i.v. and 18 IU/kg/h continous i.v., titrated to a target aPTT of 1.5–2
Enoxaparin 1 mg/kg every 12 h Dalteparin 100 U/kg every 12 h Dalteparin 200 U/kg once daily Tinzaparin 175 U/kg once daily
FIGURE 1. Treatment of venous thromboembolism during pregnancy. LMWH, low molecular weight heparin; s.c., subcutaneous; UFH, unfractionated heparin.
epidural anesthesia. UFH elimination half-life is estimated in 4–6 h, and aPTT monitoring can confirm the restoration of a normal coagulation function. A precautionary measure, however, recommended a 12–24 h discontinuation before anesthesia and childbirth. If LMWH is conversely being used, the American Society of Regional Anesthesia and Pain Medicine guidelines [45] recommend to perform epidural anesthesia not earlier than 10–12 h after the last LMWH administration if low dose, or than 20–24 h, if full dose. With regard to caesarean delivery, the recent American College of Obstetricians guidelines recommend pneumatic compression treatment for all women undergoing caesarean section and prophylactic drug therapy in addition to pneumatic compression only for women who will undergo caesarean delivery with multiple risk factors [46] (Fig. 2).
MANAGEMENT OF POSTPARTUM In women affected by VTE during pregnancy, it appears appropriate to continue the anticoagulant treatment for about a 6 month period from the onset of VTE episode and 6 weeks after delivery. It is believed that, to minimize rebleeding risk, anticoagulant administration should not take place 4–6 h after natural childbirth and 6–12 h after caesarean delivery [47]. In women who require 472
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anticoagulation for more than 6 weeks after delivery, when postpartum bleeding risk is overcome (1 to 2 weeks after birth), warfarin can be newly administered, as it is breastfeeding-compatible [48] like LMWH. On the other hand, in women who require a shorter anticoagulation therapy time limited to 6 weeks postpartum, usefulness of warfarin employment is limited as requiring a 1 to 2 weeks administration period before reaching the therapeutic range. In these circumstances, a LMWH administration schedule appears therefore preferable (Fig. 3).
THE MATTER OF DEBATE There is an ongoing debate about whether thromboprophylaxis for VTE in pregnancy is cost-effective and beneficial. Pharmacological methods may cause adverse effects that could be sufficiently severe or common to outweigh the benefits of thromboprophylaxis. Heparin is believed to be well tolerated for the fetus; however, it can cause adverse effects for the mother, such as thrombocytopenia, bleeding, allergic reactions and symptomatic osteoporosis, in the longer term. When used after caesarean section, heparin may increase the frequency of bleeding and wound complications. Originally, UFH was used, but this now appears to have been largely superseded, at least for use in pregnancy and postnatally, Volume 26 Number 6 December 2014
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Venous thromboembolism during delivery
Women already under anticoagulants
Women not under anticoagulants
Planning the delivery and stop anticoagulation around the time of labor
Caesarean section
Vaginal/caesarean delivery
Pneumatic compression for all women
LMWH should be replaced with UFH
If LMWH is being used
UHF should be discontinued 12–24 h before anesthesia and childbirth
At low dose
Anesthesia not earlier than 10–12 h
Vaginal delivery
No antithrombotic attention if not already considered during pregnancy
Add prophylactic drug therapy for women at increase risk
At full dose
Anesthesia not earlier than 20–24 h
FIGURE 2. Treatment of venous thromboembolism during delivery. LMWH, low molecular weight heparin; UFH, unfractionated heparin.
Venous thromboembolism during postpartum
Women already under anticoagulants for VTE
Women not under anticoagulants
Treatment for about 6 month period from the onset of VTE episode and at least 6 weeks after delivery
Risk stratification
If for >6 weeks after delivery: warfarin
If for 6 weeks after delivery: LMWH
One major risk factor or at least two minor risk factors
Yes
None
Anticoagulation for 6 weeks after delivery
Medical surveillance
FIGURE 3. Treatment and prophylaxis of venous thromboembolism during postpartum. LMWH, low molecular weight heparin; VTE, venous thromboembolism. 1040-872X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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by LMWH. The advantages of LMWH over UFH include a longer half-life, high bioavailability, and predictable anticoagulant response, avoiding the need for dose adjustment or laboratory monitoring in most patients. In addition, LMWHs are thought to be associated with a lower risk of adverse effects (e.g., osteoporosis and thrombocytopenia). Warfarin is known to cause congenital abnormalities and it has, therefore, rarely been used in the first trimester or in the last few weeks of pregnancy. Both heparin and warfarin have been used for postnatal thromboprophylaxis, as they have been considered as well tolerated for mothers who are breastfeeding [48]. Many methods of prophylaxis carry a risk of adverse effects and it is possible that the benefits of thromboprophylaxis may be outweighed by harms. Current guidelines for clinical practice are based largely on expert opinion, rather than high-quality evidence from randomized trials. It is therefore important to examine the use of thromboprophylaxis in women who are pregnant or have recently given birth and are at increased risk of VTE, exploring both the incidence of VTE and adverse effects of treatment.
CONCLUSION There is insufficient evidence on which to base recommendations for thromboprophylaxis during pregnancy and the early postnatal period, and large scale randomized trials of currently used interventions should be conducted. Thus, practitioners must rely on consensus-derived clinical practice guidelines or recommendations, such as those produced or endorsed by the Royal College of Obstetricians and Gynaecologists and the National Institute for Health and Care Excellence in the United Kingdom, the American College of Chest Physicians, the Australian National Medical Research Council, the Society of Obstetric Medicine of Australia and New Zealand and the Australasian Society of Thrombosis and Haemostasis and other international bodies. Acknowledgements None. Conflicts of interest The authors declare that there are no conflicts of interest.
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2. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year populationbased study. Ann Intern Med 2005; 143:697–706. 3. Bates SM. Pregnancy-associated venous thromboembolism: prevention and treatment. Semin Hematol 2011; 48:271–284. 4. Pomp ER, Lenselink AM, Rosendaal FR, et al. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6:632–637. 5. Samuelsson E, Hedenmalm K, Persson I. Mortality from venous thromboembolism in young Swedish women and its relation to pregnancy and use of oral contraceptives-an approach to specifying rates. Eur J Epidemiol 2005; 20:509–516. 6. Cahill AG, Stout MJ, Macones GA, et al. Diagnosing pulmonary embolism in pregnancy using computed-tomographic angiography or ventilation-perfusion. Obstet Gynecol 2009; 114:124–129. 7. Gherman RB, Goodwin TM, Leung B, et al. Incidence, clinical characteristics, and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999; 94:730–734. 8. Merhi Z, Awonuga A. Acute abdominal pain as the presenting symptom of isolated iliac vein thrombosis in pregnancy. Obstet Gynecol 2006; 107:460– 470. 9. Eichinger S, Weltermann A, Philipp K, et al. Prospective evaluation of hemostatic system activation and thrombin potential in healthy pregnant women with and without factor V Leiden. Thromb Haemost 1999; 82:1232–1236. 10. Ulander VM, Lehtola A, Kaaja R. Long-term outcome of deep venous thrombosis during pregnancy treated with unfractionated heparin or low molecular weight heparin. Thromb Res 2003; 111:239–242. 11. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol 2005; 193:216– 219. 12. Gordon M. Maternal physiology in pregnancy. In: Gabbe S, Niebyl J, Simpson J, editors. Normal and problem pregnancies. New York: Churchill Livingstone; 2002. pp. 63–92. ; 4. 13. Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obstet Gynecol 1997; 104:191–197. 14. Whitty J, Dombrowski M. Respiratory diseases in pregnancy. In: Gabbe S, Niebyl J, Simpson J, editors. Normal and problem pregnancies. New York: Churchill Livingstone; 2002. pp. 1033–1064. ; 4. 15. Danilenko-Dixon DR, Heit JA, Silverstein MD, et al. Risk factors for deep vein thrombosis and pulmonary embolism during pregnancy or post partum: a population-based, case control study. Am J Obstet Gynecol 2001; 184:104– 110. 16. Carr MH, Towers CV, Eastenson AR, et al. Prolonged bedrest during pregnancy: does the risk of deep vein thrombosis warrant the use of routine heparin prophylaxis? J Matern Fetal Med 1997; 6:264–267. 17. Kovacevich GJ, Gaich SA, Lavin JP, et al. The prevalence of thromboembolic events among women with extended bed rest prescribed as part of the treatment for premature labor or preterm premature rupture of membranes. Am J Obstet Gynecol 2000; 182:1089–1092. 18. James AH. Pregnancy-associated thrombosis. Hematology Am Soc Hematol Educ Program 2009; 11:277–285. 19. Lepercq J, Conard J, Borel-Derlon A. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG 2001; 108:1134–1140. 20. Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999; 94:595–599. 21. Simpson EL, Lawrenson RA, Nightingale AL, et al. Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors from a London perinatal database. BJOG 2001; 108:56–60. 22. Larsen TB, Sorensen HT, Gislum M, et al. Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case control study. Thromb Res 2007; 120:505– 509. 23. Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium: a register-based case-control study. Am J Obstet Gynecol 2008; 198:231–237. 24. Hague WM, Dekker GA. Risk factors for thrombosis in pregnancy. Best Pract Res Clin Haematol 2003; 16:197–210. 25. Sia WW, Powrie RO, Cooper AB, et al. The incidence of deep vein thrombosis in women undergoing cesarean delivery. Thromb Res 2009; 123:550– 555. 26. Barco S, Nijkeuter M, Middeldorp S. Pregnancy and venous thromboembo& lism. Semin Thromb Hemost 2013; 39:549–558. This review provides the latest insights into the current knowledge on pregnancy and thromboembolic complications. 27. Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008; 359:2025–2033. 28. Leung AN, Bull TM, Jaeschke R, et al. ATS/STR Committee on Pulmonary Embolism in Pregnancy. American Thoracic Society Documents: an official American Thoracic Society/Society of Thoracic Radiology Clinical Practice Guideline: evaluation of suspected pulmonary embolism in pregnancy. Radiology 2012; 262:635–646.
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38. Bain E, Wilson A, Tooher R, et al. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev 2014; CD001689. There is insufficient evidence on which to base recommendations for thromboprophylaxis during pregnancy and the early postnatal period. Large-scale randomized trials of currently used interventions should be conducted. 39. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins,for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106:401–407. 40. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophylia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141:e691s–e736s. 41. Pettila V, Leinonen P, Markkola A, et al. Postpartum bonemineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost 2002; 87:182–186. 42. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians evidence-based clinical practice guidelines (8th Edition). Chest 2008; 133:844S–886S. 43. American College of Obstetricians and Gynecologists. Practice Bulletin No. 123: thromboembolism in pregnancy. Obstet Gynecol 2011; 118:718–729. 44. Hague WM, North RA, Gallus AS, et al. Anticoagulation in pregnancy and the puerperium. Med J Aust 2001; 175:258–263. 45. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Executive summary: regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 2010; 35:102–105. 46. James A. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol 2011; 118:718–729. 47. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human, milk. Pediatrics 2001; 108:776–789. 48. Bauersachs RM. Treatment of venous thromboembolism during pregnancy. Thromb Res 2009; 123 (Suppl 2):S45–S50.
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Pregnancy and venous thromboembolism Eleonora Ralli a, Luigi Zezza b, and Donatella Caserta a
Purpose of review This review provides a concise and complete overview of diagnostic work-up and treatment of venous thromboembolism in pregnancy, with attention to recent research developments and recent applicable guidelines. This may be useful for all the players of the multidisciplinary interaction needed in this disease management, namely cardiologists and gynecological/obstetric teams. Recent findings Venous thromboembolism is, in the developed world, a major cause of maternal morbidity and mortality during pregnancy or early after delivery, with a reported incidence ranging from 0.49 to 2.0 events per 1000 deliveries. It is a particularly challenging issue and there is no common consensus on the major themes of this condition. Diagnostic options, prophylaxis and management, in the antenatal, childbirth and postnatal periods, are carefully analyzed in the light of the most recent published data. Besides, old and recent knowledge must be seen through the clinician’s skilled and watchful eyes, deciding on a case-tocase and actively contributing in reducing pregnancy-related morbidity. Summary Although there is an ongoing debate on various aspects of this condition and there is a paucity of highquality studies, this review attempts to simplify the complex aspects of joining safety and efficacy in diagnosing and treating a possible two-people life-threatening disease. Keywords pregnancy, thromboprophylaxis, venous thromboembolism
INTRODUCTION Venous thromboembolism (VTE) is, in developed countries, a major cause of maternal morbidity and mortality during pregnancy and postpartum, with a reported incidence ranging from 1 to 2 events per 1000 deliveries. This article briefly reviews the areas of controversy and provides recommendations for the treatment and prophylaxis of VTE in pregnant patients. Strong evidence for the management of pregnancy-related VTE is still missing, mostly because pregnant women have been excluded from all major trials investigating different diagnostic tools and treatment regimens. Nevertheless, proper evaluation of the involved risk factors is mandatory to reduce the incidence of pregnancy-related VTE and to improve outcomes. With regard to future research, large-scale randomized trials of currently used interventions should be conducted.
EPIDEMIOLOGY AND RISK FACTORS VTE is a condition in which the blood clots inappropriately. The term VTE encompasses a continuum, including both deep vein thrombosis (DVT) and pulmonary embolism [1]. VTE episodes are four to five-fold higher [2,3] during pregnancy than in a
nonpregnant status at the same age, and it is the leading cause of maternal mortality in the developed world. An even 20-fold to 80-fold higher VTE risk has been reported within the first 6 weeks following delivery [2,4,5]. The overall incidence of thromboembolic events in pregnancy is about 1 to 2 per 1000 deliveries [2,6–8]. About 80% of pregnancy-associated VTE episodes is represented by isolated DVT and about 20% of them by pulmonary embolism [2]. Normal pregnancy is known to be associated with a hypercoagulable state characterized by increased concentrations of some procoagulant factors (e.g., factors VII, VIII, X, von Willebrand factor and fibrinogen) and by a simultaneous
a
Department of Obstetrics, Gynecological and Urological Sciences and Unit of Cardiology, Clinical and Molecular Medicine Department, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy b
Correspondence to Eleonora Ralli, MD, Department of Obstetrics, Gynecological and Urological Sciences, Sant’Andrea Hospital, Sapienza University of Rome, via di Grottarossa 1035–1039, 00189, Rome, Italy. Tel: +39 063 377 5696; fax: +39 063 377 6660; e-mail: eleonora. [email protected], [email protected], [email protected] Curr Opin Obstet Gynecol 2014, 26:469–475 DOI:10.1097/GCO.0000000000000115
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KEY POINTS VTE is, in industrialized countries, a major cause of maternal morbidity and mortality during pregnancy or early after delivery.
pregnancy. Clinical decision rules using typical signs and symptoms (leg swelling, tachycardia, tachypnea and dyspnea) have never been validated in pregnant patients. The cornerstone of diagnosing pregnancy VTE is the demonstration of presence of the clot [26 ]. D-dimer testing is not currently included in several diagnostic algorithms of suspected pulmonary embolism in both pregnancy and early postpartum period [27,28]; it is considered only in the work-up of suspected iliac DVT diagnosis, when positive in the presence of negative leg compression ultrasound, a condition in which MRI of the pelvic vessels is advised [27,29]. However, in the presence of a considerably high D-dimer value, the first further recommended diagnostic step is a venous Doppler ultrasound of the lower limbs. If positive, diagnosis can be considered completed as the treatment for both clinical entities (DVT and pulmonary embolism) is similar, and radiological second level examinations, involving a radiological risk, appear to be not acceptable to both the fetus and the mother [30]. In case of a negative Doppler examination, additional diagnostic tests must be performed, which should be different in pregnant women as compared with those normally used in the general population. A debate also exists with regard to the diagnostic value of lower limb venous echo color Doppler. Chest X-ray remains crucial for the next diagnostic path, allowing clinicians to choose either between computed tomography (CT) angiography and lung perfusion scintigraphy, when normal, or suggesting the choice of combined ventilation/perfusion scan scintigraphy, when abnormal. With regard to the ideal diagnostic path to be followed, published data remain, however, inconsistent and contradictory, as studies comparing the two diagnostic techniques are characterized by an extremely low sample size [31]. Considering the comparable diagnostic accuracy of the two imaging modalities [31], the choice is often guided by a careful multidisciplinary clinical evaluation. Patients with history of renal failure or of contrast allergy certainly avail themselves of the use of pulmonary scintigraphy. Furthermore, considering the increased exposure of breast tissue following the use of angio-CT, lung perfusion scintigraphy is to be preferred in patients with normal radiographic examination and with low probability of presence of additional lung diseases [31,32]. The risks arising from exposure to ionizing radiation may be avoided when MRI is considered for diagnostic purposes. However, this technique has a largely inferior diagnostic accuracy compared with angio-CT and scintigraphy [33] and requires use of gadolinium, which has not yet been adequately studied in pregnancy as to possible fetal damage, although it has been &
A multidisciplinary approach is needed in this disease management (cardiologists and obstetrics/ gynecologists). Diagnosis, prophylaxis and management, of this condition is particularly challenging. There is no common consensus on the major themes of this disease.
decrease of other anticoagulant factors, such as protein C and protein S [9]. When DVT occurs during pregnancy, it is more likely to be proximal, massive [10] and in the left lower extremity [11]. Apart from hypercoagulability, other pregnancyrelated physiological changes become key factors for development of VTE, such as an increased venous capacitance, a decreased venous outflow [12,13], vein mechanical obstruction due to the uterus [14], decreased mobility [15–17] and increased vascular injury [3,7]. Of note, the most important risk factor for development of VTE in pregnancy is represented by a history of thromboembolic events. Recurrent VTE represents about onethird of VTE events in pregnancy [18]. An additional VTE risk factor, able to complete the recognition of women with excessive VTE hazard, is congenital or acquired thrombophilia. The risk of a thromboembolic event occurring during pregnancy has been shown to differ according to the nature of the thrombophilia, varying from 5 to 33% [4]. Among patient characteristics, predictors of VTE have been recognized in multiparity [19], AfroAmerican race [20] and age more than 35 years [3,19,20]. There is also a strong association between cigarette smoking and an increased VTE risk in pregnancy [21–23]. The use of assisted reproductive technologies [24], or the presence of gestational diabetes, preeclampsia [3,21–23], transfusions [23], infections during the postpartum period [11] and bleeding in pre and postpartum periods [21,23,24] have been described as complications of pregnancy and childbirth associated with an increased VTE risk. Furthermore, caesarean section is associated with an increased VTE risk, especially in the emerging setting [25].
DIAGNOSTIC CHANCES The use of diagnostic algorithms for VTE in nonpregnant patients is not adequate when applied in 470
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sporadically used for the diagnosis of placenta accreta and leiomyoma without reported harmful fetal effects [34]. The recent introduction of realtime MRI, using ‘fast imaging with steady-state precession’, not susceptible to motion artifacts and not requiring gadolinium, has been able to provide promising results with high sensitivity (85%) and specificity (98%) in nonpregnant patients [34] and in few diagnostic trials of pulmonary embolism in pregnancy, even if it still requires adequate validation.
MANAGEMENT There is currently broad agreement, as shown in a recent review by Okoroh et al. [35], that women should be assessed for VTE risk preconception and again during pregnancy in order to guide VTE thromboprophylaxis. Inconsistencies in international guidelines include advice regarding which group of women to offer thromboprophylaxis to, and which options should be offered to pregnant women and the duration of prophylaxis also vary. Women who have had a previous episode of VTE may, for example, be recommended long-term antenatal prophylaxis as well as prolonged postnatal prophylaxis, whereas women undergoing caesarean section may, for example, only be recommended postnatal prophylaxis for a few days. Options for VTE thromboprophylaxis include both pharmacologic agents and nonpharmacologic methods. Pharmacologic agents that have been used include the following: unfractionated heparin (UFH) or low molecular weight heparin (LMWH), aspirin, a platelet aggregation inhibitor, warfarin, a vitamin K antagonist, hydroxyethyl starch, a nonionic starch derivative, fondaparinux, a selective inhibitor of activated factor X and danaparoid, a heparinoid. Mechanical methods that have been used include the following: graduated compression stockings, intermittent pneumatic compression, venous foot pumps, early mobilization and surveillance [36,37].
MANAGEMENT DURING PREGNANCY: LOW MOLECULAR WEIGHT HEPARIN AND UNFRACTIONATED HEPARIN AT COMPARISON The most indicated drugs for treatment and VTE prevention in pregnancy are heparins [38 ]. Both forms, UFH and LMWH, are unable to cross the placental barrier and they are not secreted in breast milk in significant amounts [38 ]. LMWH is generally used for prophylaxis. It is still unknown if dose, adjusted by weight, renal function and therapeutic target, requires further correction in pregnant women. Some experts argue the need to monitor periodically, about every &
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1–3 months, the anti-Xa activity levels, 4–6 h after injection, and adjust dose in order to maintain the levels of anti-Xa activity in the range of 0.6–1.0 IU/ml. Among the potential advantages, the most important is a lower rate of bleeding [39]. Moreover, LMWH administration has been shown to be associated with a lower risk of heparininduced thrombocytopenia [40], less harmful bone tissue effect [41] and lower allergic response risk. The only disadvantage is the long half-life that can lead to childbirth complications. Four possible dosages are recommended by American College of Chest Physicians guidelines, graded across the levels of both thrombotic and hemorrhagic risks. The first and lower is the prophylactic LMWH dose, represented by enoxaparin 4000 IU or dalteparin 5000 IU or tinzaparin 4500 IU or nadroparin 2850 IU subcutaneously every 24 h (at extremes of body weight, modification of dose may be required). The second advised dosage is the intermediate-dose LMWH, consisting in enoxaparin 4000 IU or dalteparin 5000 IU subcutaneously every 12 h possibly used in prophylaxis of conditions at higher thrombotic risk. The third and fourth advised dosages are those of adjusted-dose LMWH, represented by a weight-adjusted or a full-treatment dose of LMWH, respectively, administered once daily or b.i.d. and consisting in enoxaparin 1 mg/kg every 12 h or dalteparin 100 U/kg every 12 h or dalteparin 200 U/kg once daily or tinzaparin 175 U/kg once daily [42] (Fig. 1). UFH is used mainly for therapeutic purposes; intravenous (i.v.) UFH administration in the form of sodium heparin is recommended at adequately weight-corrected doses of 80 IU/kg in bolus i.v. and 18 IU/kg/h continous i.v. administration, titrated to a target activated partial thromboplastin time (aPTT) of 1.5–2 [42] (Fig. 1). In particular, in the acute treatment of VTE happening in proximity of operative or vaginal delivery, UFH use appears to be preferred to that of LMWH. Its subcutaneous form, namely calcium heparin, has proven less effective and its effect less predictable in relation to dose.
MANAGEMENT OF LABOR AND DELIVERY In women treated with LMWH, this drug should be replaced with UFH in the last month of pregnancy or as soon as possible, if delivery is imminent [43]. Moreover, delivery should be planned and the time during which anticoagulant therapy is stopped around the time of labor should be minimized [44]. For vaginal delivery, the need of UFH, a drug with shorter half-life, complies not only with the aim of reducing bleeding risk during childbirth but, more importantly, with that of minimizing the risk of epidural hematoma at the spinal site during
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Venous thromboembolism in pregnancy
Low-dose anticoagulation
Prophylaxis
Treatment
LMWH
UFH
Intermediate anticoagulation
s.c. every 24 h: Enoxaparin 4000 IU Dalteparin 5000 IU Tinzaparin 4500 IU Nadroparin 2850 IU
s.c. every 12 h: Enoxaparin 4000 IU Dalteparin 5000 IU
Full-dose anticoagulation
80 IU/kg in bolus i.v. and 18 IU/kg/h continous i.v., titrated to a target aPTT of 1.5–2
Enoxaparin 1 mg/kg every 12 h Dalteparin 100 U/kg every 12 h Dalteparin 200 U/kg once daily Tinzaparin 175 U/kg once daily
FIGURE 1. Treatment of venous thromboembolism during pregnancy. LMWH, low molecular weight heparin; s.c., subcutaneous; UFH, unfractionated heparin.
epidural anesthesia. UFH elimination half-life is estimated in 4–6 h, and aPTT monitoring can confirm the restoration of a normal coagulation function. A precautionary measure, however, recommended a 12–24 h discontinuation before anesthesia and childbirth. If LMWH is conversely being used, the American Society of Regional Anesthesia and Pain Medicine guidelines [45] recommend to perform epidural anesthesia not earlier than 10–12 h after the last LMWH administration if low dose, or than 20–24 h, if full dose. With regard to caesarean delivery, the recent American College of Obstetricians guidelines recommend pneumatic compression treatment for all women undergoing caesarean section and prophylactic drug therapy in addition to pneumatic compression only for women who will undergo caesarean delivery with multiple risk factors [46] (Fig. 2).
MANAGEMENT OF POSTPARTUM In women affected by VTE during pregnancy, it appears appropriate to continue the anticoagulant treatment for about a 6 month period from the onset of VTE episode and 6 weeks after delivery. It is believed that, to minimize rebleeding risk, anticoagulant administration should not take place 4–6 h after natural childbirth and 6–12 h after caesarean delivery [47]. In women who require 472
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anticoagulation for more than 6 weeks after delivery, when postpartum bleeding risk is overcome (1 to 2 weeks after birth), warfarin can be newly administered, as it is breastfeeding-compatible [48] like LMWH. On the other hand, in women who require a shorter anticoagulation therapy time limited to 6 weeks postpartum, usefulness of warfarin employment is limited as requiring a 1 to 2 weeks administration period before reaching the therapeutic range. In these circumstances, a LMWH administration schedule appears therefore preferable (Fig. 3).
THE MATTER OF DEBATE There is an ongoing debate about whether thromboprophylaxis for VTE in pregnancy is cost-effective and beneficial. Pharmacological methods may cause adverse effects that could be sufficiently severe or common to outweigh the benefits of thromboprophylaxis. Heparin is believed to be well tolerated for the fetus; however, it can cause adverse effects for the mother, such as thrombocytopenia, bleeding, allergic reactions and symptomatic osteoporosis, in the longer term. When used after caesarean section, heparin may increase the frequency of bleeding and wound complications. Originally, UFH was used, but this now appears to have been largely superseded, at least for use in pregnancy and postnatally, Volume 26 Number 6 December 2014
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Pregnancy and venous thromboembolism Ralli et al.
Venous thromboembolism during delivery
Women already under anticoagulants
Women not under anticoagulants
Planning the delivery and stop anticoagulation around the time of labor
Caesarean section
Vaginal/caesarean delivery
Pneumatic compression for all women
LMWH should be replaced with UFH
If LMWH is being used
UHF should be discontinued 12–24 h before anesthesia and childbirth
At low dose
Anesthesia not earlier than 10–12 h
Vaginal delivery
No antithrombotic attention if not already considered during pregnancy
Add prophylactic drug therapy for women at increase risk
At full dose
Anesthesia not earlier than 20–24 h
FIGURE 2. Treatment of venous thromboembolism during delivery. LMWH, low molecular weight heparin; UFH, unfractionated heparin.
Venous thromboembolism during postpartum
Women already under anticoagulants for VTE
Women not under anticoagulants
Treatment for about 6 month period from the onset of VTE episode and at least 6 weeks after delivery
Risk stratification
If for >6 weeks after delivery: warfarin
If for 6 weeks after delivery: LMWH
One major risk factor or at least two minor risk factors
Yes
None
Anticoagulation for 6 weeks after delivery
Medical surveillance
FIGURE 3. Treatment and prophylaxis of venous thromboembolism during postpartum. LMWH, low molecular weight heparin; VTE, venous thromboembolism. 1040-872X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
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by LMWH. The advantages of LMWH over UFH include a longer half-life, high bioavailability, and predictable anticoagulant response, avoiding the need for dose adjustment or laboratory monitoring in most patients. In addition, LMWHs are thought to be associated with a lower risk of adverse effects (e.g., osteoporosis and thrombocytopenia). Warfarin is known to cause congenital abnormalities and it has, therefore, rarely been used in the first trimester or in the last few weeks of pregnancy. Both heparin and warfarin have been used for postnatal thromboprophylaxis, as they have been considered as well tolerated for mothers who are breastfeeding [48]. Many methods of prophylaxis carry a risk of adverse effects and it is possible that the benefits of thromboprophylaxis may be outweighed by harms. Current guidelines for clinical practice are based largely on expert opinion, rather than high-quality evidence from randomized trials. It is therefore important to examine the use of thromboprophylaxis in women who are pregnant or have recently given birth and are at increased risk of VTE, exploring both the incidence of VTE and adverse effects of treatment.
CONCLUSION There is insufficient evidence on which to base recommendations for thromboprophylaxis during pregnancy and the early postnatal period, and large scale randomized trials of currently used interventions should be conducted. Thus, practitioners must rely on consensus-derived clinical practice guidelines or recommendations, such as those produced or endorsed by the Royal College of Obstetricians and Gynaecologists and the National Institute for Health and Care Excellence in the United Kingdom, the American College of Chest Physicians, the Australian National Medical Research Council, the Society of Obstetric Medicine of Australia and New Zealand and the Australasian Society of Thrombosis and Haemostasis and other international bodies. Acknowledgements None. Conflicts of interest The authors declare that there are no conflicts of interest.
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