Thrombophilia and pregnancy complications

Summary

The implications of currently available data on the association of gestational vascular complications with thrombophilia are presented in this consensus report. Screening is recommended for women with the following previous complications: fetal loss including three or more first trimester loss, two or more second trimester loss, or any stillbirth; early, severe or recurrent preeclampsia and severe intrauterine growth restriction. Maternal antithrombotic therapy is currently evaluated in women with thrombophilia and previous complications.

On behalf of the Scientific Subcommittee on Perinatal and Pediatric Hemostasis and Working Group on Women’s health Issues and Standardization Committee of the International Society of Thrombosis and Hemostasis.

Keywords

Thrombophilia - pregnancy - antithrombotic therapy - fetal loss

• References

• 1 Triplett DA, Harris EN. Antiphospholipid antibodies and reproduction. Am J Reprod Immunol 1989; 21: 123-31.
• 2 Sanson BJ, Friederich PW, Simioni P. et al. The risk of abortion and stillbirth in antithrombin, protein C, and protein S-deficient women. Thromb Haemost 1996; 75: 387-8.
• 3 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia: report on a study of the SSC Subcommittee of Fibrinogen. Thromb Haemost 1995; 73: 151-61.
• 4 Press RD, Bauer KA, Kujovich JL. et al. Clinical utility of Factor V Leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders. Arch Path Lab Med 2002; 126: 1304-18.
• 5 Rey E, Kahn SR, David M. et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-8.
• 6 Meinardi JR, Middeldorp S, de Kam PJ. et al. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130: 736-9.
• 7 Tormene D, Simioni P, Prandoni P. et al. The risk of fetal loss in family members of probands with factor V Leiden mutation. Thromb Haemost 1999; 82: 1237-9.
• 8 Brenner B, Sarig G, Weiner Z. et al. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82: 6-9.
• 9 Younis JS, Brenner B, Ohel G. et al. Activated protein C resistance and factor V Leiden mutation can be associated with first-as well as second-trimester recurrent pregnancy loss. Am J Reprod Immunol 2000; 43: 31-5.
• 10 Sarig G, Younis JS, Hoffman R. et al. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002; 77: 342-7.
• 11 Martinelli I, Taioli E, Cetin I. et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343: 1015-18.
• 12 Kovalevsky G, Gracia CR, Berlin JA. et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis. Arch Intern Med 2004; 164: 558-63.
• 13 Nelen WL, Blom HJ, Steegers EAP. et al. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000; 74: 1196-9.
• 14 Preston FE, Rosendaal FR, Walker ID. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
• 15 Marietta M, Fachinetti F, Sgarbi L. et al. Elevated plasma levels of factor VIII in women with early recurrent miscarriage. J Thromb Haemost 2003; 01: 2536-9.
• 16 Hutado V, Montes R, Gris JC. et al. Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for foetal death. Blood. 2004 May 18 [Epub ahead of print].
• 17 Kupferminc MJ, Eldor A, Steinman N. et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med 1999; 340: 9-13.
• 18 Morrison ER, Miedzybrodzka ZH, Campbell DM. et al. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large populationbased study and systematic review. Thromb Haemost 2002; 87: 779-85.
• 19 Kupferminc MJ, Many A, Bar-Am A. et al. Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia. BJOG 2002; 109: 1373-6.
• 20 Infante-Rivard C, Rivard GE, Yotov WV. et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med 2002; 347: 19-25.
• 21 Weiner-Megnagi Z, Ben-Shlomo I, Goldberg Y. et al. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998; 179: 1565-7.
• 22 de Vries JIP, Dekker GA, Huijgens PC. et al. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997; 104: 1248-54.
• 23 Goddijn-Wessel TA, Wouters MG, van de Molen EF. et al. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996; 66: 23-9.
• 24 Vollset SE, Refsum H, Irgens LM. et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study. Am J Clin Nutr 2000; 71: 962-8.
• 25 Gris JC, Quere I, Monpeyroux F. et al. Casecontrol study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent: the Nimes Obstetricians and Haematologists Study 5 (NOHA5). Thromb Haemost 1999; 81: 891-9.
• 26 Sanson BJ, Lensing AWA, Prins MH. et al. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 668-72.
• 27 Brenner B, Hoffman R, Blumenfeld Z. et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 693-7.
• 28 Brenner B. Clinical management of thrombophilia-related placental vascular complications. Blood 2004; 103: 4003-9.
• 29 Brenner B. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications - Yes. J Thromb Haemost 2003; 01: 2070-2.
• 30 Middeldorp S. Antithrombotic prophylaxis for women with thrombophilia and pregnancy complications - No. J Thromb Haemost 2003; 110: 2073-4.
• 31 Brenner B, Hoffman R, Carp H. et al. Enoxaparin treatment improves the gestational outcome of pregnant women with thrombophilia and recurrent pregnancy loss: The LIVE-ENOX study. Blood. 2003 104. abstr. 43, P16a.
• 32 Gris JC, Mercier E, Quere I. et al. Lowmolecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 3695-9.
• 33 Vossen CY, Preston FE, Conard J. et al. Hereditary thrombophilia and fetal loss: a prospective following study. J Thromb Haemost 2004; 02: 592-6.
• 34 Hoke M, Kyrle PA, Philipp K. et al. Prospective evaluation of coagulation activation in pregnant women receiving low-molecular weight heparin. Thromb Haemost 2004; 91: 935-40.
• 35 Verspyck E, Le Camp-Duchez V, Gravier A. et al. Small for gestational age infant in association with maternal prothrombin gene variant (nt 20210A). Eur J Obstet Gynecol Reprod Biol 1999; 83: 143-4.
• 36 Kries von R, Junker R, Oberle D. et al. Foetal growth restriction in children with prothrombotic risk factors. Thromb Haemost 2001; 86: 1012-6.
• 37 Vries de LS, Eken P, Groenendaal F. et al. Antenatal onset of haemorrhagic and/or ischaemic lesions in preterm infants: prevalence and associated obstetric variables. Arch Dis Child 1998; 78: F51-F56.
• 38 Kraus FT, Acheen VI. Fetal thrombotic vasculopathy in the placenta: cerebral thrombi and infarcts, coagulopathies, and cerebral palsy. Hum Pathol 1999; 30: 759-69.
• 39 Debus O, Koch HG, Kurlemann G. et al. Factor V Leiden and genetic defects of thrombophilia in childhood porencephaly. Arch Dis Child 1998; 78: F121-F124.
• 40 Thorarensen O, Ryan S, Hunter J. et al. Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis. Ann Neurol 1997; 42: 372-5.