Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall

Medscape Reference Reference

News Reference Education MEDLINE

Anticoagulants and Thrombolytics in Pregnancy

Author: Farheen M Shah-Khan, MD; Chief Editor: Richard A Lange, MD more... Updated: Jan 12, 2011

Overview
Outline of antithrombotic agents
Although the formation of a thrombus or clot within a blood vessel is important for maintaining hemostasis, pathological thrombosis can occur and cause deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, or myocardial infarction (MI). The images below show an overview of the process for diagnosing DVT and PE, respectively.

Diagnosis of deep vein thrombosis during pregnancy.

Diagnosis of pulmonary embolism during pregnancy.

1 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall

Antithrombotic agents (ie, anticoagulants and thrombolytic agents) are first-line therapy for pathological thromboses. Anticoagulants interrupt the coagulation cascade to prevent thrombus formation and extension while endogenous thrombus lysis occurs. They are available in oral or parenteral forms. Thrombolytic agents promote thrombus lysis and are administered parenterally. Warfarin is an oral anticoagulant that interferes with liver synthesis of vitamin K-dependent clotting factors, which leads to depletion of factors II (prothrombin), VII, IX, and X and prolongation of clotting times (ie, international normalized ratio [INR]). Rivaroxaban is an orally active factor Xa inhibitor that prolongs prothrombin time (PT) and activated partial thromboplastin time (aPTT). Dabigatran is an orally administered direct thrombin inhibitor that results in prolongation of the aPTT. Unlike warfarin, the pharmacokinetics of rivaroxaban and dabigatran are predictable; thus, routine monitoring of coagulation parameters is not required when one of these agents is used. Although warfarin has been used extensively in pregnancy, the safety and efficacy of the newer oral agents (rivaroxaban or dabigatran) in pregnancy has not been established. The most commonly used parenteral anticoagulants inactivate thrombin and/or factor Xa without depleting circulating levels of clotting factors. Unfractionated heparin, low molecular weight heparin (LMWH), heparinoids, synthetic pentasaccharide inhibitors (eg, fondaparinux), and direct thrombin inhibitors (ie, hirudin and argatroban) belong to this category. Thrombolytic agents mediate the dissolution of fibrin clots by promoting the conversion of plasminogen to plasmin, which causes degradation of fibrin to fibrin degradation products. Traditional thrombolytic agents include streptokinase (SK), anisoylated plasminogen streptokinase activator complex (APSAC), urokinase, and recombinant tissue plasminogen activator (t-PA).

Evidenced indications for the use of antithrombotic agents

Indications of antithrombotic use have been recently published and include the following: Acute and chronic venous thromboembolism (including pulmonary embolism ) Atrial fibrillation Valvular and structural heart disease Ischemic stroke Acute coronary syndromes Peripheral artery occlusive disease Pregnancy is associated with 4 times increased risk of venous thromboembolism (VTE) and the risk increases to 14-fold during puerperium.
[2] [1]

This risk further increases if an underlying thrombophilia is present. PE remains a

[3] [4]

leading cause of maternal mortality in the Western world. nonpregnant women of the same age.

The risk in pregnant women is 5 times higher than in

Anticoagulant therapy is indicated in pregnancy for the treatment acute VTE, valvular heart disease, and for the prevention of pregnancy-related complications in women with antithrombin deficiency or antiphospholipid antibody syndrome (APLAs) and other thrombophilias who have had prior VTE.
[5 , 6 ]

Pathophysiology
Normal pregnancy is associated with a hypercoagulable state due, at least in part, to increased serum levels of procoagulants, such as factor II, decrease during pregnancy, trimesters of pregnancy.
[12] [7]

VII,

[7, 8]

VIII,

[7]

X,

[7, 9, 10]

XII,

[9, 10]

and fibrinogen.

[7, 11]

In addition, protein S levels

and increased resistance to activated protein C is observed in the second and third

Concomitantly, serum plasminogen activator inhibitor-1 (PAI-1) and placental plasminogen activator inhibitor-2 Venous stasis resulting from (PAI-2) increase with pregnancy which leads to a decreased fibrinolytic state.{Ref12} pressure of the gravid uterus on the inferior vena cava and decreased venous tone are additional predisposing factors to VTE.
[13]

Epidemiology of Venous Thromboembolism in Pregnancy

2 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall
[14, 15]

The incidence of pregnancy-associated VTE is estimated at 1 in 500 to 2000 deliveries (0.05-0.2%). incidence of VTE in puerperium and pregnancy is 7.19 and 0.97 per 1000 women, respectively. the prothrombin mutation (15-fold increase),
[20] [18]

4-fold to 50-fold higher in pregnant women than in nonpregnant women and is highest during puerperium.

[16, 17]

The risk is The

[19]

The risk of

pregnancy-related VTE is particularly high in heterozygous carriers of factor V Leiden (4-fold to 16-fold increase),

and women with antiphospholipid antibodies (5% incidence).{{Ref 6}

Most (approximately 85%) of DVT of the lower extremity occur on the left side during pregnancy. This is attributed to the more tortuous course of the venous drainage of the left leg through the pelvis and compression of the left common iliac vein by the overlying right iliac artery.
[21]

Prevention and Treatment of Venous Thromboembolism

The following recommendations are part of the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotics and Thrombolytics Therapy: Evidence Based Guidelines.
[22]

Table 1. ACCP Risk Factors and Recommendations (Open Table in a new window) Risk Factor Women with a single episode of VTE associated with a transient risk factor that is no longer present Women with a single episode of VTE and thrombophilia (confirmed laboratory abnormality) and a strong family history of thrombosis who are not receiving long-term anticoagulants Women with thrombophilia (other than antithrombin deficiency) and no previous VTE Women with multiple ( 2) episodes of VTE who are not receiving long-term anticoagulants Women with multiple ( 2) episodes of VTE who are receiving long-term anticoagulants All women with previous DVT, antenatal and postpartum Women with recurrent pregnancy loss ( 3 miscarriages) and women with severe or recurrent preeclampsia, placental abruption, or otherwise unexplained intrauterine growth retardation Women with antiphospholipid antibody syndrome and a history of multiple ( 2) early pregnancy losses or 1 late pregnancy losses, preeclampsia, intrauterine growth retardation (IUGR), or abruption Women with APLAs and a history of VTE who are usually receiving long-term oral anticoagulation therapy * If the previous risk factor is pregnancy or estrogenrelated or additional risk factors (such as obesity) are present, antenatal anticoagulant prophylaxis is recommended. The following are ACCP recommendations for antithrombotic agents. following 2 alternative approaches are reasonable:
[22]

Recommendations Clinical surveillance and anticoagulant prophylaxis postpartum* Prophylactic or intermediate-dose LMWH or unfractionated heparin (UFH), plus postpartum anticoagulation for at least 6 wk (for a total minimum duration of therapy of 6 mo) Clinical surveillance or prophylactic LMWH or UFH and anticoagulant prophylaxis postpartum* Prophylactic, intermediate-dose or adjusted-dose UFH or adjusted-dose LMWH followed by long-term anticoagulation postpartum Adjusted-dose UFH or LMWH followed by resumption of long-term anticoagulation postpartum Use of graduated elastic compression stockings Screen for thrombophilia and antiphospholipid antibodies

Women with antithrombin deficiency and no previous VTE Antepartum and postpartum prophylaxis

Antepartum aspirin plus prophylactic or intermediate-dose UFH or LMWH

Adjusted-dose LMWH or UFH therapy plus low-dose aspirin and resumption of long-term oral anticoagulation therapy postpartum

In pregnant women with acute VTE, the

Subcutaneous LMWH can be used initially and for long-term treatment with dose adjustment based on monitoring of anti-Xa levels.

3 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall

Intravenous (IV) UFH bolus is followed by continuous infusion to maintain aPTT in the therapeutic range for at least 5 days, followed by subcutaneous LMWH or dose-adjusted subcutaneous UFH for the remainder of pregnancy. LMWH is preferred over UFH for the prevention and treatment of VTE because of ease of use and better efficacy and safety profile. Anticoagulants should be administered for at least 6 weeks postpartum (for a minimum total duration of therapy of 6 mo). In women receiving dose-adjusted LMWH or UFH therapy, discontinuing anticoagulant therapy 24 hours prior to elective induction of labor is recommended. If spontaneous labor occurs, careful monitoring of aPTT or anti-Xa levels is required. If aPTT is markedly prolonged near delivery, protamine sulfate may be required to reduce the risk of bleeding.

Anticoagulation During Pregnancy in Patients With Valvular Heart Disease

Women with valvular heart disease who are pregnant or planning to conceive require careful evaluation and management. Physiologic changes associated with pregnancy are poorly tolerated in some cases of valvular heart disease. These include aortic stenosis, mitral regurgitation, aortic regurgitation with New York Heart Association (NYHA) class 3-4 symptoms, mitral stenosis with NYHA class 2-4 symptoms, valvular heart disease that results in severe pulmonary hypertension, and left ventricular (LV) dysfunction with an ejection fraction (EF) less than 40%. Patients with mechanical prosthetic valve requiring anticoagulation are exposed to special risks during pregnancy. Therefore, whenever possible, symptomatic or severe valvular lesions should be addressed before conception.

[23]

Treatment
Anticoagulation is recommended in most pregnant patients with a mechanical prosthetic heart valve, whereas those with a bioprosthetic valve do not require anticoagulation. Warfarin (Coumadin) is more efficacious than UFH for thromboembolic prophylaxis of pregnant women with mechanical valves. Unfortunately, warfarin therapy in the first trimester of pregnancy is associated with a substantial increase in fetal anomalies, and anticoagulation with any agent is associated with an increased incidence of fetal wastage (approximately 30%), prematurity (approximately 45%), and low birth weight (approximately 50%).
[25, 26, 22] [24]

In a systematic review of fetal and maternal outcome of pregnancy with mechanical heart valves, the regimen associated with the lowest risk of valve thrombosis (3.9%) was warfarin throughout pregnancy. However, its use throughout pregnancy was associated with warfarin embryopathy in 6.4% of live births. The substitution of heparin at or prior to 6 weeks, and continued until 12 weeks, eliminated the risk of warfarin embryopathy. Using heparin only from 6-12 weeks' gestation was associated with an increased risk of valve thrombosis (9.2%). In 2002, the US Food and Drug Administration (FDA) issued a warning that LMWH was not recommended for thromboprophylaxis in pregnant women with prosthetic heart valves. However, a consensus panel concluded that

this recommendation was based on studies in which underdosing or inadequate monitoring of LMWH occurred. Consequently, the panel supports the use of LMWH as a treatment option with monitoring of anti-Xa levels. Seshadhri et al reviewed 120 articles and concluded that LMWH, compared with UFH, may be a safe and effective agent in patients with mechanical prosthetic heart valves.
[28]

[27]

However, large-scale, randomized trials are warranted.

Recommendations
Recommendations for anticoagulation of pregnant women with prosthetic heart valves is based on the Eighth ACCP Conference on Antithrombotics and Thrombolytics and are as follows:
[22]

Adjusted dose twice daily (bid) subcutaneous LMWH throughout pregnancy to achieve a peak anti-Xa level of 1-1.2 U/mL 4 hours after injection or Adjusted dose bid subcutaneous UFH throughout pregnancy to achieve mid-interval aPTT at least twice control or an anti-Xa level of 0.35-0.70 U/mL or UFH or LMWH (as above) until 13 weeks' gestation, change to warfarin until the middle of the third trimester, and then restart UFH or LMWH

4 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall

Long-term anticoagulants should be resumed postpartum with all regimens. High-risk women with prosthetic heart valves, such as women with LV dysfunction and women with prior thromboembolic episodes, should have the addition of low-dose aspirin 75-162 mg/d.

Maternal and Fetal Complications Secondary to Anticoagulation

Use of anticoagulants in the breastfeeding mother
Heparin and LMWHs are not secreted into breast milk and can be safely administered to women who are breastfeeding.
[29]

Two reports show that maternal administration of warfarin does not induce an anticoagulant effect in the breastfed infant. Thus, women using this drug should be encouraged to breastfeed.
[29, 30]

Fetal complications of anticoagulants during pregnancy

Warfarin crosses the placenta and can cause both fetal bleeding and teratogenicity, with the latter occurring mainly during the first trimester.
[32] [31] [33, 34]

Neither UFH nor LMWH cross the placenta; therefore, these agents do not cause fetal bleeding or teratogenicity, although bleeding at the uteroplacental junction and fetal wastage is possible.

Maternal complications of anticoagulants during pregnancy

The rate of major bleeding in patients treated with UFH therapy is 2%.
[35]

Approximately 3% of patients receiving UFH develop immune thrombocytopenia (so called, heparin-induced thrombocytopenia [HIT]), which predisposes to venous and arterial thrombosis.
[36]

Heparin-induced osteoporosis causes vertebral fracture in 2-3% of patients and significant reduction in bone density is seen in about 30% of patients receiving long-term UFH. LMWH causes less osteoporosis and HIT than UFH.
39, 40, 41]

[37, 38,

Author Farheen M Shah-Khan, MD Fellow, Department of Nephrology, Northwestern Memorial Hospital Disclosure: Nothing to disclose. Coauthor(s) Nishith K Singh, MBBS, MD Resident Physician, Department of Internal Medicine, Southern Illinois University School of Medicine Nishith K Singh, MBBS, MD, is a member of the following medical societies: American College of Physicians, American Heart Association, American Medical Association, and Illinois State Medical Society Disclosure: Nothing to disclose. Nasaraiah Nallamothu, MD, FACC Clinical Assistant Professor, Department of Internal Medicine, Division of Cardiology, Southern Illinois University School of Medicine; Consulting Staff, Prairie Cardiovascular Consultants, Ltd

Contributor Information and Disclosures

5 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall

Disclosure: Nothing to disclose. Teresa Marino, MD Assistant Professor, Attending Physician, Division of Maternal-Fetal Medicine, Tufts Medical Center Disclosure: Nothing to disclose. Specialty Editor Board Serdar H Ural, MD Associate Professor of Obstetrics and Gynecology and Radiology, Director, Division of Maternal-Fetal Medicine, Medical Director, Labor and Delivery Suite, Penn State University College of Medicine Serdar H Ural, MD is a member of the following medical societies: American Association of Gynecologic Laparoscopists, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, Association of Professors of Gynecology and Obstetrics, and Society for Maternal-Fetal Medicine Disclosure: GSK Honoraria Speaking and teaching; J&J Honoraria Speaking and teaching Francisco Talavera, PharmD, PhD Senior Pharmacy Editor, eMedicine Disclosure: eMedicine Salary Employment Ronald J Oudiz, MD, FACP, FACC, FCCP Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Director, Liu Center for Pulmonary Hypertension, Division of Cardiology, LA Biomedical Research Institute at Harbor-UCLA Medical Center Ronald J Oudiz, MD, FACP, FACC, FCCP is a member of the following medical societies: American College of Cardiology, American College of Chest Physicians, American College of Physicians, American Heart Association, and American Thoracic Society Disclosure: Actelion Grant/research funds Clinical Trials + honoraria; Encysive Grant/research funds Clinical Trials + honoraria; Gilead Grant/research funds Clinical Trials + honoraria; Pfizer Grant/research funds Clinical Trials + honoraria; United Therapeutics Grant/research funds Clinical Trials + honoraria; Lilly Grant/research funds Clinical Trials + honoraria; LungRx Clinical Trials + honoraria; Bayer Grant/research funds Consulting David Chelmow, MD Leo J Dunn Distinguished Professor and Chair, Department of Obstetrics and Gynecology, Virginia Commonwealth University Medical Center David Chelmow, MD is a member of the following medical societies: American College of Obstetricians and Gynecologists, American Medical Association, Association of Professors of Gynecology and Obstetrics, Massachusetts Medical Society, Phi Beta Kappa, Sigma Xi, Society for Gynecologic Investigation, and Society for Medical Decision Making Disclosure: Nothing to disclose. Chief Editor Richard A Lange, MD Professor and Executive Vice Chairman, Department of Medicine, Director, Office of Educational Programs, University of Texas Health Science Center at San Antonio Richard A Lange, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American Heart Association, and Association of Subspecialty Professors Disclosure: Nothing to disclose.

References
1. Hirsh J, Guyatt G, Albers GW, Harrington R, Schnemann HJ, American College of Chest Physician. Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. Jun 2008;133(6 Suppl):110S-112S. [Medline].

6 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall

2. Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost. Aug 1999;82(2):610-9. [Medline]. 3. The National Institute for Clinical Excellence, Scottish Executive Health Department and Department of Health, Social Services and Public Safety: Northern Ireland. Confidential Enquiries into Maternal Deaths in the United Kingdom 1997-99. London TSO: 2001. 4. Prevention of venous thrombosis and pulmonary embolism. NIH Consensus Development. JAMA. Aug 8 1986;256(6):744-9. [Medline]. 5. Bonow RO, Carabello B, de Leon AC, Edmunds LH Jr, Fedderly BJ, Freed MD. ACC/AHA Guidelines for the Management of Patients With Valvular Heart Disease. Executive Summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Valvular Heart Disease). J Heart Valve Dis. Nov 1998;7(6):672-707. [Medline]. 6. Antiphospholipid syndrome. Practice Bulletin No. 118. American College of Obstetricians and Gynecologists. Obstet Gynecol. 2011;117:1929. 7. Stirling Y, Woolf L, North WR, Seghatchian MJ, Meade TW. Haemostasis in normal pregnancy. Thromb Haemost. Oct 31 1984;52(2):176-82. [Medline]. 8. Dalaker K, Prydz H. The coagulation factor VII in pregnancy. Br J Haematol. Feb 1984;56(2):233-41. [Medline]. 9. Condie RG. A serial study of coagulation factors XII, XI and X in plasma in normal pregnancy and in pregnancy complicated by pre-eclampsia. Br J Obstet Gynaecol. Aug 1976;83(8):636-9. [Medline]. 10. Hellgren M, Blombck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition. Gynecol Obstet Invest. 1981;12(3):141-54. [Medline]. 11. Bonnar J, McNicol GP, Douglas AS. Fibrinolytic enzyme system and pregnancy. Br Med J. Aug 16 1969;3(5667):387-9. [Medline]. 12. Fernandez JA, Estelles A, Gilabert J, Espana F, Aznar J. Functional and immunologic protein S in normal pregnant women and in full-term newborns. Thromb Haemost. Jun 30 1989;61(3):474-8. [Medline]. 13. Halligan A, Bonnar J, Sheppard B, Darling M, Walshe J. Haemostatic, fibrinolytic and endothelial variables in normal pregnancies and pre-eclampsia. Br J Obstet Gynaecol. Jun 1994;101(6):488-92. [Medline]. 14. Letsky E, de Swiet M. Annotation. Thromboembolism in pregnancy and its management. Br J Haematol. Aug 1984;57(4):543-52. [Medline]. 15. Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med. Jul 11 1996;335(2):108-14. [Medline]. 16. Prevention of venous thrombosis and pulmonary embolism. NIH Consensus Development. JAMA. Aug 8 1986;256(6):744-9. [Medline]. 17. Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost. Aug 1999;82(2):610-9. [Medline]. 18. Martinelli I. Thromboembolism in women. Semin Thromb Hemost. Oct 2006;32(7):709-15. [Medline]. 19. Grandone E, Margaglione M, Colaizzo D, D'Andrea G, Cappucci G, Brancaccio V. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obstet Gynecol. Nov 1998;179(5):1324-8. [Medline]. 20. Hibbard BM, Anderson MM, Drife JO. Report on Confidential Enquiries into Maternal Deaths in the United Kingdom 1991-93. London: HMSO; 1996. 21. McColl MD, Ramsay JE, Tait RC, Walker ID, McCall F, Conkie JA. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost. Oct 1997;78(4):1183-8. [Medline].

7 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

http://emedicine.medscape.com/article/164069-overview#showall

22. Bates SM, Greer IA, Pabinger I, Sofaer S, Hirsh J. Venous Thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy; American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:844S-886S. 23. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons, Bonow RO, Carabello BA. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation. Aug 1 2006;114(5):e84-231. [Medline]. 24. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. Jan 24 2000;160(2):191-6. [Medline]. 25. Born D, Martinez EE, Almeida PA, Santos DV, Carvalho AC, Moron AF. Pregnancy in patients with prosthetic heart valves: the effects of anticoagulation on mother, fetus, and neonate. Am Heart J. Aug 1992;124(2):413-7. [Medline]. 26. Meschengieser SS, Fondevila CG, Santarelli MT, Lazzari MA. Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart. Jul 1999;82(1):23-6. [Medline]. 27. The Anticoagulation in Prosthetic Valves and Pregnancy Consensus Report Panel and Scientific Roundtable. Anticoagulation and enoxaparin use in patients with prosthetic heart valves and/or pregnancy. Fetal-Maternal Medicine Consensus Reports. 2002;3:1. 28. Seshadri N, Goldhaber SZ, Elkayam U, Grimm RA, Groce JB 3rd, Heit JA. The clinical challenge of bridging anticoagulation with low-molecular-weight heparin in patients with mechanical prosthetic heart valves: an evidence-based comparative review focusing on anticoagulation options in pregnant and nonpregnant patients. Am Heart J. Jul 2005;150(1):27-34. [Medline]. 29. O'Reilly R. Anticoagulant, antithrombotic and thrombolytic drugs. In: Gillman AG, Goodman LS, Gilman A. The Pharmacologic basis of therapeutics. 6 ed. New York, NY: Macmillan; 1980:1347. 30. Orme ML, Lewis PJ, de Swiet M, Serlin MJ, Sibeon R, Baty JD. May mothers given warfarin breast-feed their infants?. Br Med J. Jun 18 1977;1(6076):1564-5. [Medline]. 31. McKenna R, Cole ER, Vasan U. Is warfarin sodium contraindicated in the lactating mother?. J Pediatr. Aug 1983;103(2):325-7. [Medline]. 32. Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. Jan 1980;68(1):122-40. [Medline]. 33. Flessa HC, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol. Oct 15 1965;93(4):570-3. [Medline]. 34. Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res. Jun 15 1984;34(6):557-60. [Medline]. 35. Forestier F, Daffos F, Rainaut M, Toulemonde F. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thromb Haemost. Apr 7 1987;57(2):234. [Medline]. 36. Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P, Burrows R. Heparin therapy during pregnancy. Risks to the fetus and mother. Arch Intern Med. Oct 1989;149(10):2233-6. [Medline]. 37. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. May 18 1995;332(20):1330-5. [Medline]. 38. Douketis JD, Ginsberg JS, Burrows RF, Duku EK, Webber CE, Brill-Edwards P. The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study. Thromb Haemost.
th

8 of 9

30/12/2012 12:55 PM

Anticoagulants and Thrombolytics in Pregnancy

Feb 1996;75(2):254-7. [Medline].

http://emedicine.medscape.com/article/164069-overview#showall

39. Dahlman TC. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol. Apr 1993;168(4):1265-70. [Medline]. 40. Muir JM, Andrew M, Hirsh J, Weitz JI, Young E, Deschamps P. Histomorphometric analysis of the effects of standard heparin on trabecular bone in vivo. Blood. Aug 15 1996;88(4):1314-20. [Medline]. 41. Shaughnessy SG, Hirsh J, Bhandari M, Muir JM, Young E, Weitz JI. A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treatment in rats. Blood. Feb 15 1999;93(4):1231-6. [Medline]. 42. BIEZENSKI JJ, MOORE HC. Fibrinolysis in normal pregnancy. J Clin Pathol. Jul 1958;11(4):306-10. [Medline]. 43. Ginsberg JS, Bates SM. Management of venous thromboembolism during pregnancy. J Thromb Haemost. Jul 2003;1(7):1435-42. [Medline]. 44. Ginsberg JS, Hirsh J, Rainbow AJ, Coates G. Risks to the fetus of radiologic procedures used in the diagnosis of maternal venous thromboembolic disease. Thromb Haemost. Apr 25 1989;61(2):189-96. [Medline]. 45. Mihaljevic T, Paul S, Leacche M, Rawn JD, Cohn LH, Byrne JG. Valve replacement in women of childbearing age: influences on mother, fetus and neonate. J Heart Valve Dis. Mar 2005;14(2):151-7. [Medline]. 46. Muir JM, Hirsh J, Weitz JI, Andrew M, Young E, Shaughnessy SG. A histomorphometric comparison of the effects of heparin and low-molecular-weight heparin on cancellous bone in rats. Blood. May 1 1997;89(9):3236-42. [Medline]. 47. Nijkeuter M, Ginsberg JS, Huisman MV. Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy: a systematic review. J Thromb Haemost. Mar 2006;4(3):496-500. [Medline]. 48. Nishida H, Takahara Y, Takeuchi S, Mogi K, Murayama H. Long-term evaluation of bovine pericardial bioprostheses in young women: influence of pregnancy. Jpn J Thorac Cardiovasc Surg. Oct 2005;53(10):557-61. [Medline]. 49. Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost. Oct 2004;92(4):747-51. [Medline]. 50. Greer, John P, et al. Wintrobe's Clinical Hematology. 11 ed. Philadelphia: Lippincott Williams & Wilkins; 2004. Medscape Reference 2011 WebMD, LLC
th

9 of 9

30/12/2012 12:55 PM