Semin Thromb Hemost 2009; 35(7): 630-643
DOI: 10.1055/s-0029-1242717
© Thieme Medical Publishers

Role of Thrombophilia in Adverse Obstetric Outcomes and Their Prevention Using Antithrombotic Therapy

Elvira Grandone1 , Michela Tomaiuolo1 , Donatella Colaizzo1 , Paul R.J Ames2 , Maurizio Margaglione1 , 3
  • 1Atherosclerosis and Thrombosis Unit, I.R.C.C.S. “Casa Sollievo dela Sofferenza,” S. Giovanni R. (FG), Italy
  • 2Department of Haematology, Royal Preston Hospital, Preston and Immunoclot Ltd, Leeds, United Kingdom
  • 3Medical Genetics, University of Foggia, Foggia, Italy
Further Information

Publication History

Publication Date:
09 December 2009 (online)

ABSTRACT

A series of case-control studies in the last decade have shown the role of inherited thrombophilia in the occurrence of adverse obstetric outcomes. In small series of cases, it has been proven that rare inherited causes of thrombophilia such as natural anticoagulant deficiencies can be associated with fetal losses. The confirmed presence of antiphospholipid antibodies in plasma, representing an acquired thrombophilic condition, is also an established cause of fetal losses, although other studies with a smaller sample size have found an association with other obstetric complications, namely preeclampsia, fetal growth restriction, and abruption placentae. Case-control studies have been performed regarding the potential association between unexplained fetal losses and mild hyperhomocysteinemia. Although case-control and prospective studies are also available regarding hyperhomocysteinemia and other gestational vascular complications, published data are conflicting. Intervention studies have been performed to prevent adverse obstetric outcomes in women with inherited or acquired thrombophilia and previous adverse outcomes. There is much debate in the literature regarding the need for treatment of women with thrombophilia during pregnancy. Although in most cases these are not randomized controlled trials, all studies found significantly better outcomes in treated pregnancies compared with those of untreated pregnancies.

REFERENCES

  • 1 De Stefano V, Rossi E, Leone G. Inherited thrombophilia, pregnancy, and oral contraceptive use: clinical implications.  Semin Vasc Med. 2003;  3(1) 47-60
  • 2 Ku D H, Arkel Y S, Paidas M P, Lockwood C J. Circulating levels of inflammatory cytokines (IL-1 beta and TNF-alpha), resistance to activated protein C, thrombin and fibrin generation in uncomplicated pregnancies.  Thromb Haemost. 2003;  90(6) 1074-1079
  • 3 Clark P, Brennand J, Conkie J A, McCall F, Greer I A, Walker I D. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy.  Thromb Haemost. 1998;  79(6) 1166-1170
  • 4 Stirling Y, Woolf L, North W R, Seghatchian M J, Meade T W. Haemostasis in normal pregnancy.  Thromb Haemost. 1984;  52(2) 176-182
  • 5 Comp P C, Thurnau G R, Welsh J, Esmon C T. Functional and immunologic protein S levels are decreased during pregnancy.  Blood. 1986;  68(4) 881-885
  • 6 Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis in pregnancy, during delivery and in the puerperium. I. Normal condition.  Gynecol Obstet Invest. 1981;  12(3) 141-154
  • 7 Stirling Y, Woolf L, North W R, Seghatchian M J, Meade T W. Haemostasis in normal pregnancy.  Thromb Haemost. 1984;  52(2) 176-182
  • 8 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(4) 1232-1236
  • 9 Bremme K A. Haemostatic changes in pregnancy.  Best Pract Res Clin Haematol. 2003;  16(2) 153-168
  • 10 Heit J A, Kobbervig C E, James A H, Petterson T M, Bailey K R, Melton III L J. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study.  Ann Intern Med. 2005;  143(10) 697-706
  • 11 Grandone E, Margaglione M. Inherited thrombophilia and gestational vascular complications.  Best Pract Res Clin Haematol. 2003;  16(2) 321-332
  • 12 Roberts J M, Taylor R N, Musci T J, Rodgers G M, Hubel C A, McLaughlin M K. Preeclampsia: an endothelial cell disorder.  Am J Obstet Gynecol. 1989;  161(5) 1200-1204
  • 13 Salafia C M, Pezzullo J C, López-Zeno J A, Simmens S, Minior V K, Vintzileos A M. Placental pathologic features of preterm preeclampsia.  Am J Obstet Gynecol. 1995;  173(4) 1097-1105
  • 14 Shanklin D R, Sibai B M. Ultrastructural aspects of preeclampsia. I. Placental bed and uterine boundary vessels.  Am J Obstet Gynecol. 1989;  161(3) 735-741
  • 15 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis.  Lancet. 2003;  361(9361) 901-908
  • 16 Kovalevsky G, Gracia C R, Berlin J A, Sammel M D, Barnhart K T. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss: a meta-analysis.  Arch Intern Med. 2004;  164(5) 558-563
  • 17 Griffin J H, Evatt B, Zimmerman T S, Kleiss A J, Wideman C. Deficiency of protein C in congenital thrombotic disease.  J Clin Invest. 1981;  68(5) 1370-1373
  • 18 Schwarz H P, Fischer M, Hopmeier P, Batard M A, Griffin J H. Plasma protein S deficiency in familial thrombotic disease.  Blood. 1984;  64(6) 1297-1300
  • 19 De Stefano V, Finazzi G, Mannucci P M. Inherited thrombophilia: pathogenesis, clinical syndromes, and management.  Blood. 1996;  87(9) 3531-3544
  • 20 Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism—results of the Spanish Multicentric Study on Thrombophilia (EMET-Study).  Thromb Haemost. 1997;  77(3) 444-451
  • 21 Friederich P W, Sanson B J, Simioni P et al.. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis.  Ann Intern Med. 1996;  125(12) 955-960
  • 22 Han X, Fiehler R, Broze Jr G J. Characterization of the protein Z-dependent protease inhibitor.  Blood. 2000;  96(9) 3049-3055
  • 23 Paidas M J, Ku D H, Lee M J et al.. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications.  J Thromb Haemost. 2005;  3(3) 497-501
  • 24 Gris J C, Quéré I, Dechaud H et al.. High frequency of protein Z deficiency in patients with unexplained early fetal loss.  Blood. 2002;  99(7) 2606-2608
  • 25 Grandone E, Colaizzo D, Cappucci F, D'Ambrosio R L, Vecchione G, Margaglione M. An unreported mutation within protein Z gene is associated with very low protein levels in women with fetal loss.  Fertil Steril. 2008;  90(3) 864-865
  • 26 Grandone E, Favuzzi G, De Stefano V et al.. Protein Z g-42a variant and the risk of pregnancy-related venous thromboembolism in a cohort of Italian patients.  Thromb Res. 2009;  123(6) 848-850
  • 27 Chinni E, Tiscia G L, Colaizzo D, Vergura P, Margaglione M, Grandone E. Annexin V expression in human placenta is influenced by the carriership of the common haplotype M2.  Fertil Steril. 2009;  91(3) 940-942
  • 28 Bogdanova N, Horst J, Chlystun M et al.. A common haplotype of the annexin A5 (ANXA5) gene promoter is associated with recurrent pregnancy loss.  Hum Mol Genet. 2007;  16(5) 573-578
  • 29 Tiscia G, Colaizzo D, Chinni E et al.. Haplotype M2 in the annexin A5 (ANXA5) gene and the occurrence of obstetric complications.  Thromb Haemost. 2009;  102(3) 309-313
  • 30 Ruffatti A, Tonello M, Cavazzana A, Bagatella P, Pengo V. Laboratory classification categories and pregnancy outcome in patients with primary antiphospholipid syndrome prescribed antithrombotic therapy.  Thromb Res. 2009;  123(3) 482-487
  • 31 Tincani A, Bazzani C, Zingarelli S, Lojacono A. Lupus and the antiphospholipid syndrome in pregnancy and obstetrics: clinical characteristics, diagnosis, pathogenesis, and treatment.  Semin Thromb Hemost. 2008;  34(3) 267-273
  • 32 Bates S M, Greer I A, Pabinger I, Sofaer S, Hirsh J. American College of Chest Physicians . Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).  Chest. 2008;  133(6, Suppl) 844S-886S
  • 33 Macklon N S, Greer I A. Venous thromboembolic disease in obstetrics and gynaecology: the Scottish experience.  Scott Med J. 1996;  41(3) 83-86
  • 34 James A H. Venous thromboembolism in pregnancy.  Arterioscler Thromb Vasc Biol. 2009;  29(3) 326-331
  • 35 McColl M D, Ramsay J E, Tait R C et al.. Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost. 1997;  78(4) 1183-1188
  • 36 Grandone E, Margaglione M, Colaizzo D et al.. Genetic susceptibility to pregnancy-related venous thromboembolism: roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations.  Am J Obstet Gynecol. 1998;  179(5) 1324-1328
  • 37 Biron-Andreani C, Schved J F, Daures J P, Factor V. Factor V Leiden mutation and pregnancy-related venous thromboembolism: what is the exact risk? Results from a meta-analysis.  Thromb Haemost. 2006;  96(1) 14-18
  • 38 Robertson L, Wu O, Langhorne P et al.. Thrombophilia in pregnancy: a systematic review.  Br J Haematol. 2006;  132(2) 171-196
  • 39 Lewis G 2007. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving mothers' lives: reviewing maternal deaths to make motherhood safer—2003–2005. In: The Seventh Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London, United Kingdom; CEMACH
  • 40 Brill-Edwards P, Ginsberg J S, Gent M Recurrence of Clot in This Pregnancy Study Group et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism.  N Engl J Med. 2000;  343(20) 1439-1444
  • 41 Pabinger I, Grafenhofer H, Kyrle P A et al.. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism.  Blood. 2002;  100(3) 1060-1062
  • 42 Stirrat G M. Recurrent miscarriage.  Lancet. 1990;  336(8716) 673-675
  • 43 Ventura S J, Taffel S M, Mosher W D. Estimates of pregnancies and pregnancy rates for the United States, 1976–85.  Am J Public Health. 1988;  78(5) 506-511
  • 44 Alberman E. The epidemiology of repeated abortion. In: Beard RW, Sharp F Early Pregnancy Loss: Mechanisms and Treatment. London, United Kingdom; RCOG Press 1988: 9-17
  • 45 De Braekeleer M, Dao T N. Cytogenetic studies in couples experiencing repeated pregnancy losses.  Hum Reprod. 1990;  5(5) 519-528
  • 46 Clifford K, Rai R, Watson H, Regan L. An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases.  Hum Reprod. 1994;  9(7) 1328-1332
  • 47 Grimbizis G F, Camus M, Tarlatzis B C, Bontis J N, Devroey P. Clinical implications of uterine malformations and hysteroscopic treatment results.  Hum Reprod Update. 2001;  7(2) 161-174
  • 48 Warburton D, Strobino B. Recurrent spontaneous abortion. In: Bennet MJ, Edmonds DK Spontaneous and Recurrent Abortion. Oxford, United Kingdom; Blackwell Scientific 1987: 77-78
  • 49 Sanson B J, Friederich P W, Simioni P et al.. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.  Thromb Haemost. 1996;  75(3) 387-388
  • 50 Preston F E, Rosendaal F R, Walker I D et al.. Increased fetal loss in women with heritable thrombophilia.  Lancet. 1996;  348(9032) 913-916
  • 51 Pattison N S, Chamley L W, McKay E J, Liggins G C, Butler W S. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations.  Br J Obstet Gynaecol. 1993;  100(10) 909-913
  • 52 Erkan D, Merrill J T, Yazici Y, Sammaritano L, Buyon J P, Lockshin M D. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin.  Arthritis Rheum. 2001;  44(6) 1466-1467
  • 53 Gris J C, Perneger T V, Quéré I et al.. Antiphospholipid/antiprotein antibodies, hemostasis-related autoantibodies, and plasma homocysteine as risk factors for a first early pregnancy loss: a matched case-control study.  Blood. 2003;  102(10) 3504-3513
  • 54 Lynch A, Marlar R, Murphy J et al.. Antiphospholipid antibodies in predicting adverse pregnancy outcome. A prospective study.  Ann Intern Med. 1994;  120(6) 470-475
  • 55 Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy.  Obstet Gynecol. 1995;  86(4 Pt 1) 555-559
  • 56 Erkan D, Merrill J T, Yazici Y, Sammaritano L, Buyon J P, Lockshin M D. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin.  Arthritis Rheum. 2001;  44(6) 1466-1467
  • 57 Wouters M G, Boers G H, Blom H J et al.. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss.  Fertil Steril. 1993;  60(5) 820-825
  • 58 Nelen W L, Blom H J, Steegers E A, den Heijer M, Eskes T K. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis.  Fertil Steril. 2000;  74(6) 1196-1199
  • 59 Kujovich J L. Thrombophilia and pregnancy complications.  Am J Obstet Gynecol. 2004;  191(2) 412-424
  • 60 Krause M, Sonntag B, Klamroth R et al.. Lipoprotein (a) and other prothrombotic risk factors in Caucasian women with unexplained recurrent miscarriage. Results of a multicentre case-control study.  Thromb Haemost. 2005;  93(5) 867-871
  • 61 Kupferminc M J, Eldor A, Steinman N et al.. Increased frequency of genetic thrombophilia in women with complications of pregnancy.  N Engl J Med. 1999;  340(1) 9-13
  • 62 Brenner B, Sarig G, Weiner Z, Younis J, Blumenfeld Z, Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause.  Thromb Haemost. 1999;  82(1) 6-9
  • 63 Carp H, Salomon O, Seidman D, Dardik R, Rosenberg N, Inbal A. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss.  Hum Reprod. 2002;  17(6) 1633-1637
  • 64 Lyall F, Greer I A. Pre-eclampsia: a multifaceted vascular disorder of pregnancy.  J Hypertens. 1994;  12(12) 1339-1345
  • 65 Magann E F, Martin Jr J N. Pre-clampsia/eclampsia. In: Knobil E, Neill JD Encyclopedia of Reproduction. Vol 3. San Diego, CA; Academic Press 1998: 964-970
  • 66 Saftlas A F, Olson D R, Franks A L, Atrash H K, Pokras R. Epidemiology of preeclampsia and eclampsia in the United States, 1979–1986.  Am J Obstet Gynecol. 1990;  163(2) 460-465
  • 67 Cowles T, Saleh A, Cotton D B. Hypertensive disorders of pregnancy. In: James DK, Steer PJ, Weiner CP, Gonik B High Risk Pregnancy-Management Options. London, United Kingdom; Saunders 1994: 253-275
  • 68 Sibai B M. Hypertensive disease. In: Gleicher N Principle and Practice of Medicinal Therapy in Pregnancy. Stamford, CT; Appleton and Lange 1998: 997-1022
  • 69 Redman C W. Current topic: pre-eclampsia and the placenta.  Placenta. 1991;  12(4) 301-308
  • 70 Redman C W. Platelets and the beginnings of preeclampsia.  N Engl J Med. 1990;  323(7) 478-480
  • 71 Greer I A. Pathological processes in pregnancy-induced hypertension and intrauterine growth retardation: “an excess of heated blood”. In: Greer IA, Turpie AGG, Forbes CD Haemostasis and Thrombosis in Obstetrics and Gynaecology. London, United Kingdom; Chapman and Hall 1992: 163-202
  • 72 Dizon-Townson D S, Nelson L M, Easton K, Ward K. The factor V Leiden mutation may predispose women to severe preeclampsia.  Am J Obstet Gynecol. 1996;  175(4 Pt 1) 902-905
  • 73 Nagy B, Tóth T, Rigó Jr J, Karádi I, Romics L, Papp Z. Detection of factor V Leiden mutation in severe pre-eclamptic Hungarian women.  Clin Genet. 1998;  53(6) 478-481
  • 74 Rigó Jr J, Nagy B, Fintor L et al.. Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase.  Hypertens Pregnancy. 2000;  19(2) 163-172
  • 75 Kupferminc M J, Fait G, Many A, Gordon D, Eldor A, Lessing J B. Severe preeclampsia and high frequency of genetic thrombophilic mutations.  Obstet Gynecol. 2000;  96(1) 45-49
  • 76 Grandone E, Margaglione M, Colaizzo D et al.. Factor V Leiden, C > T MTHFR polymorphism and genetic susceptibility to preeclampsia.  Thromb Haemost. 1997;  77(6) 1052-1054
  • 77 Morrison E R, Miedzybrodzka Z H, Campbell D M et al.. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review.  Thromb Haemost. 2002;  87(5) 779-785
  • 78 Kosmas I P, Tatsioni A, Ioannidis J P. Association of Leiden mutation in factor V gene with hypertension in pregnancy and pre-eclampsia: a meta-analysis.  J Hypertens. 2003;  21(7) 1221-1228
  • 79 Dekker G A, de Vries J I, Doelitzsch P M et al.. Underlying disorders associated with severe early-onset preeclampsia.  Am J Obstet Gynecol. 1995;  173(4) 1042-1048
  • 80 De Groot C J, Bloemenkamp K W, Duvekot E J et al.. Preeclampsia and genetic risk factors for thrombosis: a case-control study.  Am J Obstet Gynecol. 1999;  181(4) 975-980
  • 81 Livingston J C, Barton J R, Park V, Haddad B, Phillips O, Sibai B M. Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia.  Am J Obstet Gynecol. 2001;  185(1) 153-157
  • 82 O'Shaughnessy K M, Fu B, Ferraro F, Lewis I, Downing S, Morris N H. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase gene variants in an East Anglian preeclampsia cohort.  Hypertension. 1999;  33(6) 1338-1341
  • 83 Kim Y J, Williamson R A, Murray J C et al.. Genetic susceptibility to preeclampsia: roles of cytosineto-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine beta-synthase, and factor V Leiden mutation.  Am J Obstet Gynecol. 2001;  184(6) 1211-1217
  • 84 Laivuori H, Kaaja R, Ylikorkala O, Hiltunen T, Kontula K. 677 C—>T polymorphism of the methylenetetrahydrofolate reductase gene and preeclampsia.  Obstet Gynecol. 2000;  96(2) 277-280
  • 85 van Pampus M G, Koopman M M, Wolf H, Büller H R, Prins M H, van den Ende A. Lipoprotein(a) concentrations in women with a history of severe preeclampsia—a case control study.  Thromb Haemost. 1999;  82(1) 10-13
  • 86 Bar J, Harell D, Bardin R et al.. The elevated plasma lipoprotein(a) concentrations in preeclampsia do not precede the development of the disorder.  Thromb Res. 2002;  105(1) 19-23
  • 87 Facchinetti F, Marozio L, Frusca T et al.. Maternal thrombophilia and the risk of recurrence of preeclampsia.  Am J Obstet Gynecol. 2009;  200(1) 46.e1-5
  • 88 van Rijn B B, Hoeks L B, Bots M L, Franx A, Bruinse H W. Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia.  Am J Obstet Gynecol. 2006;  195(3) 723-728
  • 89 Sibai B M, el-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis.  Am J Obstet Gynecol. 1986;  155(5) 1011-1016
  • 90 Romo A, Carceller R, Tobajas J. Intrauterine growth retardation (IUGR): epidemiology and etiology.  Pediatr Endocrinol Rev. 2009;  6(Suppl 3) 332-336
  • 91 Martinelli P, Grandone E, Colaizzo D et al.. Familial thrombophilia and the occurrence of fetal growth restriction.  Haematologica. 2001;  86(4) 428-431
  • 92 Kupferminc M J, Many A, Bar-Am A, Lessing J B, Ascher-Landsberg J. Mid-trimester severe intrauterine growth restriction is associated with a high prevalence of thrombophilia.  BJOG. 2002;  109 1373-1376
  • 93 Grandone E, Margaglione M, Colaizzo D et al.. Lower birth-weight in neonates of mothers carrying factor V G1691A and factor II A(20210) mutations.  Haematologica. 2002;  87(2) 177-181
  • 94 de Vries J I, Dekker G A, Huijgens P C, Jakobs C, Blomberg B M, van Geijn H P. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies.  Br J Obstet Gynaecol. 1997;  104(11) 1248-1254
  • 95 Lindqvist P G, Svensson P J, Marsaál K, Grennert L, Luterkort M, Dahlbäck B. Activated protein C resistance (FV:Q506) and pregnancy.  Thromb Haemost. 1999;  81(4) 532-537
  • 96 Infante-Rivard C, Rivard G E, Yotov W V et al.. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.  N Engl J Med. 2002;  347(1) 19-25
  • 97 McCowan L M, Craigie S, Taylor R S, Ward C, McLintock C, North R A. Inherited thrombophilias are not increased in “idiopathic” small-for-gestational-age pregnancies.  Am J Obstet Gynecol. 2003;  188(4) 981-985
  • 98 Dudding T E, Attia J. The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis.  Thromb Haemost. 2004;  91 700-711
  • 99 Howley H E, Walker M, Rodger M A. A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction.  Am J Obstet Gynecol. 2005;  192(3) 694-708
  • 100 Conard J, Horellou M H, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women.  Thromb Haemost. 1990;  63(2) 319-320
  • 101 Leeda M, Riyazi N, de Vries J I, Jakobs C, van Geijn H P, Dekker G A. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction.  Am J Obstet Gynecol. 1998;  179(1) 135-139
  • 102 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(9149) 292-293
  • 103 Vollset S E, Refsum H, Irgens L M et al.. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine study.  Am J Clin Nutr. 2000;  71(4) 962-968
  • 104 Grandone E, Colaizzo D, Vecchione G et al.. Homocysteine levels in amniotic fluid. Relationship with birth-weight.  Thromb Haemost. 2006;  95(4) 625-628
  • 105 Ananth C V, Smulian J C, Vintzileos A M. Incidence of placental abruption in relation to cigarette smoking and hypertensive disorders during pregnancy: a meta-analysis of observational studies.  Obstet Gynecol. 1999;  93(4) 622-628
  • 106 Addis A, Moretti M E, Ahmed Syed F, Einarson T R, Koren G. Fetal effects of cocaine: an updated meta-analysis.  Reprod Toxicol. 2001;  15(4) 341-369
  • 107 van der Molen E F, Verbruggen B, Novakova I, Eskes T K, Monnens L A, Blom H J. Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy.  BJOG. 2000;  107 785-791
  • 108 Dizon-Townson D S, Meline L, Nelson L M, Varner M, Ward K. Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction.  Am J Obstet Gynecol. 1997;  177(2) 402-405
  • 109 Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E. Resistance to activated protein C and the Leiden mutation: high prevalence in patients with abruptio placentae.  Am J Obstet Gynecol. 1998;  179(6 Pt 1) 1565-1567
  • 110 Facchinetti F, Marozio L, Grandone E, Pizzi C, Volpe A, Benedetto C. Thrombophilic mutations are a main risk factor for placental abruption.  Haematologica. 2003;  88(7) 785-788
  • 111 Procházka M, Happach C, Marsál K, Dahlbäck B, Lindqvist P G, Factor V. Leiden in pregnancies complicated by placental abruption.  BJOG. 2003;  110 462-466
  • 112 de Vries J I, Dekker G A, Huijgens P C, Jakobs C, Blomberg B M, van Geijn H P. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies.  Br J Obstet Gynaecol. 1997;  104(11) 1248-1254
  • 113 Alfirevic Z, Roberts D, Martlew V. How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.  Eur J Obstet Gynecol Reprod Biol. 2002;  101(1) 6-14
  • 114 Goddijn-Wessel T A, Wouters M G, van de Molen E F et al.. Hyperhomocysteinemia: a risk factor for placental abruption or infarction.  Eur J Obstet Gynecol Reprod Biol. 1996;  66(1) 23-29
  • 115 Chan W S, Anand S, Ginsberg J S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature.  Arch Intern Med. 2000;  160(2) 191-196
  • 116 Orme M L, Lewis P J, de Swiet M et al.. May mothers given warfarin breast-feed their infants?.  BMJ. 1977;  1(6076) 1564-1565
  • 117 Bowles L, Cohen H. Inherited thrombophilias and anticoagulation in pregnancy.  Best Pract Res Clin Obstet Gynaecol. 2003;  17(3) 471-489
  • 118 Greer I A. Exploring the role of low-molecular-weight heparins in pregnancy.  Semin Thromb Hemost. 2002;  28(Suppl 3) 25-31
  • 119 Royal College of Obstetricians and Gynaecologists (RCOG) .Thromboprophylaxis during Pregnancy, Labour and after Vaginal Delivery. Guideline no. 37. London, United Kingdom; RCOG Press 2004
  • 120 Lussana F, Dentali F, Abbate R et al.. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines by the Italian Society of Haemostasis and Thrombosis.  Thromb Res. 2009 August 10 (Epub ahead of print); 
  • 121 Gerhardt A, Scharf R E, Beckmann M W et al.. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.  N Engl J Med. 2000;  342(6) 374-380
  • 122 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(5) 693-697
  • 123 Ogueh O, Chen M F, Spurll G, Benjamin A. Outcome of pregnancy in women with hereditary thrombophilia.  Int J Gynaecol Obstet. 2001;  74(3) 247-253
  • 124 Kupferminc M J, Fait G, Many A et al.. Low-molecular-weight heparin for the prevention of obstetric complications in women with thrombophilias.  Hypertens Pregnancy. 2001;  20(1) 35-44
  • 125 Brenner B, Hoffman R, Carp H, Dulitsky M, Younis J. LIVE-ENOX Investigators . Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE-ENOX study.  J Thromb Haemost. 2005;  3(2) 227-229
  • 126 Grandone E, Brancaccio V, Colaizzo D et al.. Preventing adverse obstetric outcomes in women with genetic thrombophilia.  Fertil Steril. 2002;  78(2) 371-375
  • 127 Rey E, Garneau P, David M et al.. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial.  J Thromb Haemost. 2009;  7(1) 58-64
  • 128 Grandone E, De Stefano V, Rossi E, Cappucci F, Colaizzo D, Margaglione M. Antithrombotic prophylaxis during pregnancy in women with deficiency of natural anticoagulants.  Blood Coagul Fibrinolysis. 2008;  19(3) 226-230
  • 129 Walker I D, Kujovich J L, Greer I A et al.. The use of LMWH in pregnancies at risk: new evidence or perception?.  J Thromb Haemost. 2005;  3(4) 778-793

Elvira GrandoneM.D. 

Atherosclerosis and Thrombosis Unit, I.R.C.C.S. “Casa Sollievo della Sofferenza,” Poliambulatorio Giovanni Paolo II

Viale Padre Pio, S. Giovanni R. (FG), Italy

Email: e.grandone@operapadrepio.it