Exploring the Role of Low-Molecular-Weight Heparins in Pregnancy

ABSTRACT

Thromboembolic complications are leading causes of both maternal and fetal morbidity and mortality. To reduce the incidence of venous thromboembolism (VTE) in pregnancy and improve outcomes, a wider understanding of the risk factors involved and better identification of women at risk of thrombosis are required. Optimal management of thromboembolic disease, both to prevent VTE and to avoid recurrence of pregnancy complications such as miscarriage, centers on the use of low-molecular-weight heparin (LMWH). LMWHs, such as enoxaparin and dalteparin, have clinical and practical advantages compared with unfractionated heparin in terms of improved safety (significantly lower incidence of osteoporosis, thrombocytopenia, and possibly allergic skin reactions) and the potential for outpatient treatment of acute VTE. However, many unanswered questions remain, including who to treat, how to treat them, and when to treat in the case of patients with thrombophilia and a history of previous pregnancy complications.

KEYWORDS

Low-molecular-weight heparin - pregnancy - venous thromboembolism - risk factors - treatment

REFERENCES

• 1 Department of Health, Welsh Office, Scottish Home and Health Department and Department of Health and Social Services Northern Ireland. Confidential Enquiries into Maternal Deaths in the United Kingdom 1997-9 London: The Stationery Office 2000
• 2 McColl M D, Ellison J, Greer I A, Tait R C, Walker I D. Prevalence of the post-thrombotic syndrome in young women with previous venous thromboembolism.  Br J Haematol . 2000;  108 272-274
• 3 Brill-Edwards P, Ginsberg J S, Gent M. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group.  N Engl J Med . 2000;  343 1439-1444
• 4 Greer I A, Thomson A J. Management of venous thromboembolism in pregnancy.  Best Pract Res Clin Obstet Gynaecol . 2001;  15 583-603
• 5 McColl M D, Ramsay J E, Tait R C. Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost . 1997;  78 1183-1188
• 6 Greer I A. The challenge of thrombophilia in maternal-fetal medicine.  N Engl J Med . 2000;  342 424-425
• 7 McColl M D, Ellison J, Reid F. Prothrombin 20210GA, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy.  Br J Obstet Gynaecol . 2000;  107 565-569
• 8 Gerhardt A, Scharf R E, Beckmann M W. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.  N Engl J Med . 2000;  342 374-380
• 9 Kupferminc M J, Eldor A, Steinman N. Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med . 1999;  340 9-13
• 10 Clark P, Brennand J, Conkie J A. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.  Thromb Haemost . 1998;  79 1166-1170
• 11 Clark P, Walker I D, Greer I. Acquired activated protein-C resistance in pregnancy and association with increased thrombin generation and fetal weight.  Lancet . 1999;  353 292-293
• 12 Clark P, Sattar N, Walker I D, Greer I A. The Glasgow Outcome, APCR and Lipid (GOAL) Pregnancy Study: significance of pregnancy associated activated protein C resistance.  Thromb Haemost . 2001;  85 30-35
• 13 Bates S M, Ginsberg J S. Anticoagulants in pregnancy: fetal effects.  Baillieres Clin Obstet Gynaecol . 1997;  11 479-488
• 14 Vitale N, De Feo M, De Santo S L. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves.  J Am Coll Cardiol . 1999;  33 1637-1641
• 15 Ginsberg J S, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest . 2001;  119 122S-131S
• 16 Wütschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention.  Drug Saf . 1999;  20 515-525
• 17 Nelson-Piercy C. Hazards of heparin: allergy, heparin-induced thrombocytopenia and osteoporosis.  Baillieres Clin Obstet Gynaecol . 1997;  11 489-509
• 18 Warkentin T E, Levine M N, Hirsh J. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.  N Engl J Med . 1995;  332 1330-1335
• 19 Ensom M H, Stephenson M D. Low-molecular-weight heparins in pregnancy.  Pharmacotherapy . 1999;  19 1013-1025
• 20 Sanson B-J, Lensing A W, Prins M H. Safety of low molecular weight heparin in pregnancy: a systematic review.  Thromb Haemost . 1999;  81 668-672
• 21 Barbour L A, Kick S D, Steiner J F. A prospective study of heparin-induced osteoporosis in pregnancy using bone densitometry.  Am J Obstet Gynecol . 1994;  170 862-869
• 22 Douketis J D, Ginsberg J S, Burrows R F. The effects of long-term heparin therapy during pregnancy on bone density. A prospective matched cohort study.  Thromb Haemost . 1996;  75 254-257
• 23 Dahlman T C. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin.  Am J Obstet Gynecol . 1993;  168 1265-1270
• 24 Monreal M, Lafoz E, Olive A, del Rio L, Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.  Thromb Haemost . 1994;  71 7-11
• 25 Shefras J, Farquharson R G. Bone density studies in pregnant women receiving heparin.  Eur J Obstet Gynecol . 1996;  65 171-174
• 26 Hunt B J, Doughty H A, Majumdar G. Thromboprophylaxis with low molecular weight heparin (Fragmin) in high risk pregnancies.  Thromb Haemost . 1997;  77 39-43
• 27 Nelson-Piercy C, Letsky E A, de Swiet M. Low-molecular weight heparin for obstetric thromboprophylaxis: experience of sixty-nine pregnancies in sixty-one women at high risk.  Am J Obstet Gynecol . 1997;  176 1062-1068
• 28 Ellison J, Walker I D, Greer I A. Antenatal use of enoxaparin for the prevention and treatment of thromboembolism in pregnancy.  Br J Obstet Gynaecol . 2000;  107 1116-1121
• 29 Lepercq J, Conard J, Borel-Derlon A. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.  Br J Obstet Gynaecol . 2001;  108 1134-1140
• 30 Thomson A J, Walker I D, Greer I A. Low-molecular-weight heparin for immediate management of thromboembolic disease in pregnancy [letter].  Lancet . 1998;  352 1904
• 31 Casele H L, Laifer S A, Woelkers D A, Venkataramanan R. Changes in the pharmacokinetics of the low-molecular-weight heparin enoxaparin sodium during pregnancy.  Am J Obstet Gynecol . 1999;  181 1113-1117
• 32 Roddre V A, Thomson A J, Stewart F M. Low molecular heparin for the treatment of venous thromboembolism in pregnancy-a case series (in press).  Br J Obstet Gynaecol. 2002; 
• 33 Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis J S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.  Thromb Haemost . 2000;  83 693-697