The Obstetrician & Gynaecologist 2007;9:1:3-8
doi: 10.1576/toag.9.1.003.27289
Copyright © 2007 by the Royal College of Obstetricians and Gynaecologists.
A clinical approach to the management of thrombosis in obstetrics. Part 2: diagnosis and treatment of venous thromboembolism
Farah Asghar, MMedSc, MRCOG, Specialist Registrar1 and
Paul Bowman, FRCOG, FRCPI, Consultant Obstetrician and Gynaecologist2
1. Coombe Women's Hospital, Dublin 8, Republic of Ireland. Email: farahasghar{at}doctors.org.uk (corresponding author)
2. Coombe Women's Hospital, Dublin 8, Republic of Ireland.
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Abstract
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Key content:- The diagnosis of venous thromboembolism requires objective testing, which can be done safely throughout pregnancy.
- Low molecular weight heparin is the most suitable agent for both prophylaxis and treatment of venous thromboembolism in pregnancy.
- Once labour has commenced, heparin should not be administered.
- It is recommended that anticoagulants be resumed 4–6 hours after vaginal delivery and 6–12 hours after caesarean delivery.
Learning objectives:
- To be able to choose the most appropriate diagnostic tests for venous thromboembolism in pregnancy.
- To be able to prescribe the most appropriate anticoagulants.
- To be able to manage women on anticoagulants appropriately during the different stages of pregnancy.
Ethical issues:
- The risks to the fetus of anticoagulant therapy are outweighed by the health benefits to the mother.
- Women of reproductive age on oral anticoagulants should know about warfarin embryopathy.
Please cite this article as: Asghar F, Bowman P. A clinical approach to the management of thrombosis in obstetrics. Part 2: diagnosis and treatment of venous thromboembolism. The Obstetrician & Gynaecologist 2007;9:3–8.
Keywords low molecular weight heparin / pregnancy / pulmonary embolism / unfractionated heparin / venous thromboembolism
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Introduction
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Pulmonary embolism remains a leading cause of maternal mortality in the Western world.1 The Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic Therapy2 has recommended reducing mortality rates by investigating women aggressively whenever there is a clinical suspicion of deep vein thrombosis (DVT) or pulmonary embolism and treating those with a diagnosis of venous thromboembolism (VTE).
The screening and prophylaxis of VTE during pregnancy were discussed in part 1 of this article.
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Diagnosis of venous thromboembolic disease in pregnancy
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Diagnosis of DVT and pulmonary embolism in pregnancy (Figures 1 and 2) is challenging because of the physiological changes which occur. Many of the classical symptoms of VTE, including tachycardia, tachypnoea, dyspnoea and leg swelling, can also be associated with a normal pregnancy.3 Therefore, high clinical suspicion is critical to diagnosis. It is important to confirm or exclude the diagnosis of VTE as it involves prolonged therapy, prophylaxis during future pregnancies and avoidance of the oral contraceptive pill. On the other hand, if untreated, 15–24% of women with venous thrombosis will develop pulmonary embolism.4 During pregnancy this is fatal in almost 15% of women, 66% of whom will die within 30 minutes of the embolic event.4
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Figure 2
Diagnosis of pulmonary embolism in pregnancy CTPA = computed tomography pulmonary angiogram; CUS = compression ultrasound
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See Box 1 for a list of diagnostic tests.
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Laboratory tests
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Arterial blood gases are neither sensitive nor specific for the diagnosis of pulmonary embolism and respiratory alkalosis is a very common feature of both pregnancy and pulmonary embolism. As in the nonpregnant population, a normal PO2, PaCO2 or alveolar–arterial difference is common with pulmonary embolism.5
D-dimer is a breakdown product of cross-linked fibrin. The sensitivity of D-dimer levels by enzyme-linked immunosorbent assay (ELISA) is quite good, with a negative predictive value of 94%.6 However, the usefulness of this test is limited by the fact that elevations in D-dimer occur in normal pregnancy, increasing with gestational age and peaking to approximately 685 ng/ml at delivery and in the early postpartum period.6 D-dimers rise significantly in women in preterm labour, or who have pre-eclampsia or placental abruption.6 Thus, a 'positive' D-dimer test in pregnancy is not necessarily consistent with VTE and objective diagnostic testing is required. However, a low level of D-dimer is likely to suggest that there is no VTE.7
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Radiographic tests
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Exposure of a pregnant woman to ionising radiation of less than a total of 5 rads (50 000 µGy) has not been associated with significant risk of fetal injury.4 There have been reports that gestational exposure to 5 rads of ionising radiation may increase the risk of some childhood cancers.4 However, most diagnostic procedures for VTE expose the fetus to a small fraction of this amount of radiation and entail only a very small risk of subsequent problems.
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Tests for deep vein thrombosis
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Doppler ultrasound
This is the test of choice during pregnancy because it is non-invasive, does not involve radiation and has largely replaced contrast venography which is invasive, less sensitive and involves radiation exposure. Compression ultrasound has shown that lack of compressibility of a thigh vein with the ultrasound probe is highly sensitive (97%) and specific (>95%) for symptomatic proximal vein thrombosis.8 Compression ultrasound, however, is less accurate for isolated calf DVT, which comprises approximately 20% of symptomatic DVTs.8 It is also inadequate when used alone for isolated iliac vein thrombosis. As these proximal thrombi carry a very high risk of embolisation, it is important to recognise those women who may need further testing in the setting of a negative ultrasound.9 If the ultrasound (compression or duplex scanning) confirms the diagnosis of DVT, anticoagulant treatment should be commenced or continued. If the ultrasound is negative and there is a low level of clinical suspicion, anticoagulant treatment can be discontinued. If the ultrasound is negative and a high level of clinical suspicion exists, the woman should be put on a course of anticoagulants and the ultrasound repeated in one week. X-ray venography should be considered. If repeat testing is negative, the anticoagulant treatment should be discontinued.
Magnetic resonance imaging (MRI)
MRI can detect both thigh and pelvic vein DVT with a sensitivity that approaches 100% in nonpregnant women. The safety of MRI during pregnancy has not been proven, although no adverse effects have been documented to date.8
X-ray contrast venography
Venography is considered the gold standard for the diagnosis of lower extremity DVT in both pregnant and nonpregnant women. However, it is rarely performed as the test uses ionising radiation and requires percutaneous cannulation of lower extremity veins and because non-invasive tests approach venography in sensitivity and specificity. Although the amount of radiation delivered to the fetus is small (<500 µGy), if it is performed with abdominal–pelvic shielding, this renders the test relatively insensitive to isolated iliofemoral thrombosis.
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Tests for pulmonary embolism
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Ventilation/perfusion (V/Q) lung scanning
Ventilation/perfusion lung scanning remains the initial diagnostic modality of choice in both pregnant and nonpregnant women for the diagnosis of pulmonary embolism.9 The amount of radiation exposure varies based on the isotope used, but all methods are within the safe range for use during pregnancy and range between 0.006--0.018 rads for the perfusion scan and between 0.001–0.035 rads for the ventilation scan.4 Results need to be interpreted in the context of pretest probability.8 In the setting of a normal V/Q scan, pulmonary embolism can safely be ruled out. If the result shows a high probability, the woman should be treated for pulmonary embolism in most circumstances. If the test is not diagnostic, pulmonary embolism cannot be excluded and further tests may be justified. The technetium-99 used in V/Q scanning is excreted by the kidneys and collects in the bladder, which increases the fetal radiation exposure by the proximity of the radioactive material. Encouraging fluid intake and frequent voiding for 4 to 6 hours after the test can minimise this exposure. Technetium-99 is also excreted in breast milk, therefore postpartum women who undergo V/Q scanning should substitute formula for breast milk for 2 days.8 This can inhibit breastfeeding, especially in the first few postpartum days. In these circumstances, other modalities can be considered.
Helical (spiral) CT scanning
Helical (spiral) CT scanning using intravenous contrast (CT angiography) for diagnosis of pulmonary embolism offers faster scanning times, increased sensitivity and better resolution. The estimated mean radiation dose to the fetus is 3–131 µGy across pregnancy: these values are lower than those calculated for V/Q scanning.10 Both the sensitivity and specificity are affected by the location of the embolus and have been reported as 100%.10 Helical CT is more sensitive for emboli in the central arteries and less sensitive for subsegmental emboli.9 Owing to its wider diagnostic entities, a CT scan may diagnose other abnormalities responsible for a woman's symptoms where pulmonary embolism is negative.
Ultimately, some women may require pulmonary arteriography to establish or exclude definitively the presence of pulmonary embolism. An MRI may also be considered in specialised centres. However, the sensitivity and specificity of this test for diagnosis of pulmonary embolism is unclear and large clinical studies comparing MRI with pulmonary arteriography are lacking.9
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Treatment of venous thromboembolism
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Heparin is the mainstay of treatment of VTE during pregnancy Figure 3. It is an indirect thrombin inhibitor which complexes with antithrombin and converts this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa and, to a lesser extent, factors XIIa, XIa and IXa.2 The main advantage of heparin compounds is that there is no transplacental passage, therefore there is no risk of fetal haemorrhage or teratogenesis.11 Intravenous unfractionated heparin has the advantages of a shorter half life and rapid effect.11 Concerns relating to sustained administration of unfractionated heparin during pregnancy include the relative difficulty of maintaining a stable therapeutic response because of its unstable pharmacokinetics. Prolonged use during pregnancy may result in osteoporosis, with a 17–36% reduction in bone density, 2% risk of vertebral fracture, 2% risk of major bleeding and a risk of heparin induced thrombocytopenia.12 An early course of heparin administration is associated with thrombocytopenia, which is usually mild, reversible and self-limiting.13 It is thought to be due to platelet aggregation as a direct effect of heparin. Heparin induced thrombocytopenia or thrombosis (HITT), on the other hand, is immune-mediated and antibodies to heparin are detectable. This condition occurs in 1–3% of nonpregnant women treated with unfractionated heparin.13 The mortality rate of untreated HITT with thromboembolic complications is 20–30%.
Treatment with heparin can also lead to bone demineralisation, which can result in the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible.12
In the treatment of acute pulmonary embolism, a loading dose of 5 000 iu followed by continuous intravenous infusion of 1 000–2 000 iu/hour is sufficient. The dose may be adjusted according to the levels of activated partial thromboplastin time (APTT) and anti-Xa.
Twelve-hourly subcutaneous unfractionated heparin is an effective alternative to intravenous unfractionated heparin for the initial management of deep vein thrombosis. It includes an initial intravenous bolus of 5 000 iu and then subcutaneous injections of 15 000–20 000 iu 12 hourly monitored by APTT. 7 Administration of protamine sulphate can work as an antidote and reduce clinical bleeding in women receiving unfractionated heparin or low molecular weight heparin.14
Low molecular weight heparin
Low molecular weight heparin (LMWH) appears to be safe for the fetus and is the agent of choice for both antenatal thromboprophylaxis and the treatment of VTE.11 Neither unfractionated heparin nor low molecular weight heparin crosses the placenta15 and there is no evidence of teratogenesis or risk of fetal haemorrhage. Heparins are not secreted in breast milk.15 While parenteral administration is still required, potential advantages of LMWH over unfractionated heparin are less bleeding, less bone loss, a lower risk of heparin induced thrombocytopenia and a long half life.16
Dosage and duration
The appropriate dosage and duration of LMWH depends on the indications for treatment of VTE or thromboprophylaxis. Because of the increased clearance rate of LMWH in pregnancy, twice daily dosing regimens are generally recommended.17 In the acute management of VTE it seems appropriate that LMWH should be used in standard doses, according to total body weight. It is not clear as to whether the dose should be based on early pregnancy weight or weight at the time of developing the VTE.
In general terms, a woman should continue anticoagulant treatment until the risk of treatment outweighs the risk of recurrent VTE. It is recommended that therapeutic anticoagulant treatment outside pregnancy should continue for 6 months. It would seem reasonable to advise the same duration during pregnancy. In women with VTE during pregnancy, many experts continue the full treatment dose for the rest of the pregnancy, while others switch to an intermediate dose after a set period. However, if VTE occurs early in the pregnancy and provided there are no additional risk factors, the dose of LMWH can be reduced to prophylactic levels for the rest of the pregnancy.15 It is recommended that anticoagulant treatment should be continued postnatally for 6–12 weeks, depending on the presence of underlying thrombophilia and other risk factors.7 At 3 months postpartum, the woman should be assessed for continuing risk factors for VTE.17
Before anticoagulant treatment is commenced, blood should be taken for a full thrombophilia screen, full blood count and coagulation screen, as well as urea, electrolytes and liver function tests to exclude renal or hepatic dysfunction.17 Although the results of a thrombophilia screen will not influence immediate management, it can provide information that can influence the duration and intensity of anticoagulation. Monitoring of treatment with anti-Xa assay can be employed to detect drug accumulation and the risk of overdose in severe renal failure.7 If therapeutic treatment with LMWH is continued, peak anti-Xa activity (3 hours post injection) should be measured. The target therapeutic range for anti-Xa is 0.6–1.0 iu/ml.17 Where the peak anti-Xa level is above the upper limit of the target therapeutic range, the dose of LMWH can be reduced. If the treatment is commenced at weekends, the monitoring of anti-Xa levels can be deferred until the next routine working day.11 The platelet count should be rechecked 7 to 9 days after commencing treatment to detect heparin induced thrombocytopenia.12
Warfarin
Warfarin crosses the placenta and, if possible, should be avoided during pregnancy or in women who may be pregnant. The critical period of organogenesis is from the fourth week to the eighth week after conception.18 Warfarin taken during this period is associated with a risk of up to 5% of teratogenesis as well as an increased risk of miscarriage, fetal and maternal haemorrhage, neurological problems in the fetus and stillbirth.18 The warfarin embryopathy includes midface hypoplasia, stippled chondral calcification, scoliosis, short proximal limbs and short phalanges.18 Warfarin is associated with a lower rate of thromboembolic complications, including mechanical valve thrombosis.18 Warfarin is not secreted in breast milk in clinically significant amounts and can be used safely in postpartum women.7, 13, 24 Following initial heparinisation in women with VTE, it can usually be initiated on the second or third postnatal day. The international normalised ratio (INR) should be checked on day two and subsequent warfarin doses titrated to maintain the INR between 2.0 and 3.0. Heparin treatment should be continued until the INR is >2.0 on two successive days.14, 17
Lepirudin and danaparoid
Lepirudin is the recombinant hirudin approved for the treatment of HITT.19 It is a direct thrombin inhibitor and can be given subcutaneously or intravenously. It crosses the placenta but there was no adverse fetal outcome in the two cases reported so far.19
Danaparoid is a heparinoid composed of heparan sulphate, dermatan sulphate and chondroitin sulphate. Its mechanism of action is not entirely clear but it inhibits factor Xa and, to a much lesser degree, thrombin.20 In about 20% of cases it exhibits in vitro cross-reactivity to the antibodies which mediate HITT but in vivo cross-reactivity is rare.20 Danaparoid has a long half life and almost 100% bioavailability. It is used for prophylaxis in patients undergoing hip replacement surgery. This agent has been used extensively in patients with HITT.20 Therapy with danaparoid is monitored by anti-factor Xa assay.
Fondaparinux
Fondaparinux, a synthetic heparin pentasaccharide, has been used for thromboprophylaxis after orthopaedic surgery.21 It catalyses factor Xa inactivation by antithrombin without inhibiting thrombin, which precludes it from causing HITT. Reports from the literature do not show transplacental passage, suggesting that it may be reasonably safe in the second and third trimester.21 Its longer acting analogue, idraparinux, which will be available in the UK from 2007, can be given only once per week.
Thrombolytics
Thrombolytic use is reserved for massive unstable pulmonary embolism. Use of thrombolytic therapy in pregnant women has been minimal and, in fact, pregnancy is considered a relative contraindication for thrombolytic therapy. However, there are case reports in the literature of thrombolysis being used safely in pregnancy,22 although its use is associated with a risk of maternal or fetal haemorrhage, teratogenesis and fetal loss. Because of these risks, the use of thrombolytics has been reserved for those cases in which the life of the mother is threatened.
Inferior vena cava filters
Inferior vena cava (IVC) filters have been successfully used during pregnancy in women with acute VTE with contraindications to anticoagulation or women with a recurrent, potentially fatal, embolism.23 They have been associated with risk of migration of the filter; perforation of the aorta, duodenum or renal pelvis; and penetration of nearby structures, including vertebrae and the retroperitoneum.
Embolectomy
Embolectomy is a treatment option for massive pulmonary embolism where conventional therapy has failed. It is indicated to prevent death in women who are haemodynamically unstable despite anticoagulation and vasopressors.23 Although data is limited for the use of embolectomy in pregnancy, early usage has been associated with a high incidence of death and neurological sequelae, therefore it must be restricted to cases in which the life of the woman is critically endangered.23
Ximelagatran
The first of a new class of oral anticoagulants, ximelagatran is a direct thrombin inhibitor. It has been widely studied and is available, initially for orthopaedic thromboprophylaxis, in some European countries.24 If it is not teratogenic and does not cross the placenta (no data was available at the time of writing), then it will prove to be an exciting and attractive alternative to LMWH.11, 24
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Peripartum management of women on anticoagulants
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The following points are important in the management of women on anticoagulants:- Immobility during pregnancy, labour and the puerperium should be minimised and dehydration avoided.
- Once labour has commenced, heparin should not be administered.
- Careful attention should be paid to the timing of LMWH injections if regional anaesthesia is required. To minimise the risk of epidural haematoma, regional techniques should not be used until 12 hours after the previous prophylactic dose and 24 hours after the last dose of a therapeutic regime of LMWH.7
- The injection of intravenous unfractionated heparin or LMWH should be avoided until at least 4 hours after removal of an epidural catheter.7
- It is recommended that anticoagulants be resumed 4–6 hours after vaginal delivery and 6–12 hours after caesarean delivery.25
- If the woman chooses to use warfarin postnatally, this can usually be initiated on the second or third postnatal day and requires close monitoring with INR tests.
- Women who have a thrombotic event during pregnancy should be continued on therapeutic anticoagulant therapy for at least 6 months post event.7
- Where a VTE occurs in early pregnancy, after completion of 6 months of therapeutic therapy the dose can be reduced to prophylactic levels and continued for 6–12 weeks following delivery, provided there are no additional risk factors.
Regarding the shorter half life of unfractionated heparin, James et al.26 have written about the experience of converting women to unfractionated heparin at 36–37 weeks of gestation or sooner if there is any evidence of imminent delivery.
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Conclusion
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The diagnosis of VTE requires objective testing, which can be done safely throughout pregnancy. Low molecular weight heparin is the most suitable agent for both prophylaxis and treatment of VTE in pregnancy and offers several advantages over unfractionated heparin. In the case of massive pulmonary embolism, thrombolytics and IVC filters are considered in nonpregnant women and may be useful in pregnancy only in life threatening conditions.
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References
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- Bates SM, Greer IA, Hirsh J, Ginsburg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126;Suppl_3:627S–644S. doi:10.1378/chest.126.3_suppl.627S
- Refuerzo JS, Hechtman JL, Redman ME, Whitty JE. Venous thromboembolism during pregnancy. Clinical suspicion warrants evaluation. J Reprod Med 2003;48:767–70.[Medline]
- Winer-Muram HT, Boone JM, Brown HL, Jennings SG, Mabie WC, Lombardo GT. Pulmonary embolism in pregnant patients: fetal radiation dose with helical CT. Radiology 2002;224:487–92.[Abstract/Free Full Text]
- Chan WS, Ginsberg JS. Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy. Thromb Res 2002;107:85–91. doi: 10.1016/S0049-3848(02)00105-6[Medline]
- Bounameaux H, de Moerloose P, Perrier A, Reber G. Plasma measurement of D-dimer as diagnostic aid in suspected venous thromboembolism: an overview. Thromb Haemost 1994;71:1–6.[Medline]
- Royal College of Obstetricians and Gynaecologists. Guideline No 28. Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management. London: RCOG; 2001. [www.rcog.org.uk/index.asp?PageID5533].
- The Royal College of Radiologists. Diagnostic Medical Exposures: Advice on Exposure to Ionising Radiation During Pregnancy; 1998. [www.hpa.org.uk/radiation/publications/misc_publications/advice_during_pregnancy.htm].
- Nijkeuter M, Ginsberg JS, Huisman V. Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy: a systematic review. J Thromb Haemost 2006;4:496–500. doi:10.1111/j.1538-7836.2005.01779.x[Medline]
- Hiorns MP, Mayo JR. Spiral computed tomography for acute pulmonary embolism. Can Assoc Radiol J 2002;53:258–68.[Medline]
- Greer I, Hunt BJ. Low molecular weight heparin in pregnancy: current issues. Br J Haematol 2005;128:593–601. doi:10.1111/j.1365-2141.2004.05304.x[Medline]
- Nelson Piercy C. Hazards of heparin allergy, heparin-induced thrombocytopenia and osteoporosis. In: Greer IA, editor. Clinical Obstetrics and Gynaecology–Thromboembolic Disease in Obstetrics and Gynaecology. London: Bailliere Tindall; 1997. p. 489–509.
- Pravinkumar E, Webster NR. HIT/HITT and alternative anticoagulation: current concepts. Br J Anaesth 2003;90:676–85. doi:10.1093/bja/aeg063[Abstract/Free Full Text]
- Bates SM, Ginsberg JS. How we manage venous thromboembolism during pregnancy. Blood 2002;100:3470–8. doi:10.1182/blood-2002-03-0965[Abstract/Free Full Text]
- Greer IA. Prevention of venous thromboembolism in pregnancy. Eur J Med Res 2004;9:135–45.[Medline]
- Casele HL, Laifer SA, Woelkers DA, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol 1999;181:1113–1117. doi:10.1016/S0002-9378(99)70091-8[Medline]
- Scottish Intercollegiate Guidelines Network. Pregnancy and the puerperium. In: In: Antithrombotic Therapy. A National Clinical Guideline. SIGN Publication No 36. Edinburgh: SIGN; 1999. [www.sign.ac.uk/pdf/sign36.pdf].
- Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systemic review of the literature. Arch Intern Med 2000;160:191–6. doi:10.1001/archinte.160.2.191[Abstract/Free Full Text]
- Huhle G, Geberth M, Hoffmann U, Heene DL, Harenberg J. Management of heparin associated thrombocytopenia in pregnancy with subcutaneous r-hirudin. Gynaecol Obsetet Invest 2000;49:67–9. doi:10.1159/000010216
- Tardy-Poncet B, Tardy B, Reynaud J, Mahul P, Mismetti P, Mazet E, et al. Efficacy and safety of danaparoid sodium (ORG 10172) in critically ill patients with heparin-associated thrombocytopenia. Chest 1999;115:1616–20. doi:10.1378/chest.115.6.1616
- Dempfle CE. Minor transplacental passage of fondaparinux in vivo. N Engl J Med 2004;350:1914–5. doi:10.1056/NEJM200404293501825[Free Full Text]
- Huang WH, Kirz DS, Gallee RC, Gordey K. First trimester use of recombinant tissue plasminogen activator in pulmonary embolism. Obstet Gynecol 2000;96:838. doi:10.1016/S0029-7844(00)00966-2[Medline]
- Ahearn GS, Hadjiliadis D, Govert JA, Tapson VE. Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options. Arch Intern Med 2002;162:1221–7. doi:10.1001/archinte.162.11.1221[Free Full Text]
- Hirsh J, O'Donnell M, Weitz JI. New anticoagulants. Blood 2005;105:453–63. doi:10.1182/blood-2003-12-4195[Abstract/Free Full Text]
- UpToDate®. Auerbach RD, Lockwood CJ. Overview of prevention of venous thrombosis in pregnant and postpartum women; 2006. [www.uptodate.com].
- James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol 2005;193:216–9.[Medline]
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Abstract
Introduction
