Thrombophilia and Adverse Pregnancy Outcome

ABSTRACT

The hemostatic system plays an important role in three crucial stages of pregnancy: ovulation, implantation, and placentation. A thrombophilic defect is an abnormality in the coagulation pathways that predisposes an individual to thrombosis. Pregnancy is a hypercoaguable state and interest has focused on the potential role that thrombophilic defects may play in the etiology not only of recurrent miscarriage but also of late pregnancy complications. Maternal intervillous blood flow does not develop to any significant extent before 8 weeks of gestation and thrombophilic defects are therefore unlikely to contribute to pregnancy loss before this time. Retrospective studies have reported a similar prevalence of genetic thrombophilic defects among women with recurrent first-trimester miscarriage and controls but an increased prevalence among those with second-trimester miscarriage and later pregnancy complications. There is a paucity of data documenting the prospective outcome of untreated pregnancies among women with thrombophilic defects and of the placental histology in these pregnancies. Until these issues have been addressed, routine thromboprophylaxis during pregnancy cannot be recommended for women with thrombophilic abnormalities.

KEYWORD

Thrombophilia - pregnancy - recurrent miscarriage

REFERENCES

• 1 Kutteh W H. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.  Am J Obstet Gynecol . 1996;  174 1584-1589
• 2 Rai R, Cohen H, David M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).  Br Med J . 1997;  314 253-257
• 3 Stirling Y, Woolf L, North W R, Seghatchian M J, Meade T W. Haemostasis in normal pregnancy.  Thromb Haemost . 1984;  52 176-182
• 4 Bonnar J. Haemostasis and coagulation disorders in pregnancy. In: Bloom A, Thomas DP, eds. Haemostasis and Thrombosis Edinburgh: Churchill Livingstone 1981: 454
• 5 Cumming A M, Tait R C, Fildes S, Yoong A, Keeney S, Hay C RM. Development of resistance to activated protein C during pregnancy.  Br J Haematol . 1995;  90 725-727
• 6 Comp P C, Thurnau G R, Welsh J, Esmon C T. Functional and immunologic protein S levels are decreased during pregnancy.  Blood . 1986;  68 881-885
• 7 de Boer K, ten Cate W J, Sturk A, Borm J J, Treffers P E. Enhanced thrombin generation in normal and hypertensive pregnancy.  Am J Obstet Gynecol . 1989;  160 95-100
• 8 Lao T T, Yuen P M, Yin J A. Protein S and protein C levels in Chinese women during pregnancy, delivery and the puerperium.  Br J Obstet Gynaecol . 1989;  96 167-170
• 9 Faught W, Garner P, Jones G, Ivey B. Changes in protein C and protein S levels in normal pregnancy.  Am J Obstet Gynecol . 1995;  172 147-150
• 10 Weenink G H, Treffers P E, Kahle L H, ten Cate W J. Antithrombin III in normal pregnancy.  Thromb Res . 1982;  26 281-287
• 11 Bremme K, Ostlund E, Almqvist I, Heinonen K, Blomback M. Enhanced thrombin generation and fibrinolytic activity in normal pregnancy and the puerperium.  Obstet Gynecol . 1992;  80 132-137
• 12 Cadroy Y, Grandjean H, Pichon J. Evaluation of six markers of haemostatic system in normal pregnancy and pregnancy complicated by hypertension or pre-eclampsia.  Br J Obstet Gynaecol . 1993;  100 416-420
• 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 . 1994;  101 488-492
• 14 Stegnar M, Zore A, Novak-Antolic Z, Vovk N, Kruithof E K. Tissue-type plasminogen activator after venous occlusion in pregnancy and puerperium.  Thromb Haemost . 1993;  70 486-490
• 15 Burgess-Wilson M E, Morrison R, Heptinstall S. Spontaneous platelet aggregation in heparinised blood during pregnancy.  Thromb Res . 1986;  41 385-393
• 16 Louden K A, Broughton P F, Heptinstall S, Fox S C, Mitchell J R, Symonds E M. Platelet reactivity and serum thromboxane B₂ production in whole blood in gestational hypertension and pre-eclampsia.  Br J Obstet Gynaecol . 1991;  98 1239-1244
• 17 Fitzgerald D J, Mayo G, Catella F, Entman S S, FitzGerald G A. Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platelets.  Am J Obstet Gynecol . 1987;  157 325-330
• 18 Horn E H, Cooper J, Hardy E, Heptinstall S, Rubin P C. A cross-sectional study of platelet cyclic AMP in healthy and hypertensive pregnant women.  Clin Sci . 1991;  80 549-558
• 19 Rushton D I. Placental pathology in spontaneous miscarriage. In: Beard RW, Sharp F, eds. Early Pregnancy Loss: Mechanisms and Treatment London: RCOG 1988: 149-158
• 20 Out H J, Kooijman C D, Bruinse H W, Derksen R H. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies.  Eur J Obstet Gynecol Reprod Biol . 1991;  41 179-186
• 21 Dizon T D, 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;  177 401-405
• 22 Preston F E, Rosendaal F R, Walker I D, Briet E, Berntorp E. Increased fetal loss in women with heritable thrombophilia.  Lancet . 1996;  348 913-916
• 23 Ramsey E M, Donner N W. Placental vasculature and circulation.  Stuttgart: George Thieme; 1980
• 24 Jauniaux E, Jurkovic D, Campbell S, Hustin J. Doppler ultrasonographic features of the developing placental circulation: correlation with anatomic findings.  Am J Obstet Gynecol . 1992;  166 585-587
• 25 Jaffe R, Woods J RJ. Color Doppler imaging and in vivo assessment of the anatomy and physiology of the early uteroplacental circulation.  Fertil Steril . 1993;  60 293-297
• 26 Coppens M, Loquet P, Kollen M, De Neubourg F, Buytaert P. Longitudinal evaluation of uteroplacental and umbilical blood flow changes in normal early pregnancy.  Ultrasound Obstet Gynecol . 1996;  7 114-121
• 27 Burton G J, Jauniau E, Watson A L. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am J Obstet Gynecol .  1999;  181 718-724
• 28 Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is assocaited with activated protein C resistance.  Br J Haematol . 1996;  92 489-490
• 29 Vincent T, Rai R, Regan L, Cohen H. Increased thrombin generation in women with recurrent miscarriage [letter].  Lancet . 1998;  352 116
• 30 Gris J C, Ripart N S, Maugard C. Respective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages: the Nimes Obstetricians and Haematologists (NOHA) Study.  Thromb Haemost . 1997;  77 1096-1103
• 31 Laskin C A, Chuma A, Angelov L. Sera from habitual aborters induce monocyte procoagulant activity: a lymphocyte-dependent event.  Clin Immunol Immunopathol . 1994;  73 235-244
• 32 Tulppala M, Marttunen M, Soderstrom-Anttila V. Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A₂ production.  Hum Reprod . 1997;  12 1567-1572
• 33 Woodhams B J, Candotti G, Shaw R, Kernoff P BA. Changes in coagulation and fibrinolysis during pregnancy: evidence of activation of coagulation preceding spontaneous abortion.  Thromb Res . 1989;  55 99-107
• 34 Rosendaal F R, Koster T, Vandenbroucke J P, Reitsma P H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood . 1995;  85 1504-1508
• 35 Hellgren M, Svensson P J, Dahlbaeck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives.  Am J Obstet Gynecol . 1995;  173 210-213
• 36 Rai R S, Regan L, Chitolie A, Donald J G, Cohen H. Plascental thrombosis and second trimester miscarriage in association with activated protein C resistance.  Br J Obstet Gynaecol . 1996;  103 842-844
• 37 Gopel W, Kim D, Gortner L. Prothrombotic mutations as a risk factor for preterm birth [letter].  Lanced . 1999;  353 1411-1412
• 38 Poort S R, Rosendaal F R, Reitsma P H, Bertina R M. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.  Blood . 1996;  88 3698-3703
• 39 Franco R F, Trip M D, ten Cate H. The 20210 G→A mutation in the 3'-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease.  Br J Haematol . 1999;  104 50-54
• 40 Sun W Y, Witte D P, Degen J L. Prothrombin deficiency results in embryonic and neonatal lethality in mice.  Proc Natl Acad Sci U S A . 1998;  95 7597-7602
• 41 Frosst P, Blom H J, Milos R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase [letter].  Nat Genet . 1995;  10 111-113
• 42 Kluijtmans L A, van den Heuvel P L, Boers G H. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease.  Am J Hum Genet . 1996;  58 35-41
• 43 Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated C resistance.  Br J Haematol . 1996;  92 489-490
• 44 Coumans A B, Juijgens P C, Jakobs C. Haemostatic and metabolic abnormalities in women with unexplained recurrent abortion.  Hum Reprod . 1999;  14 211-214
• 45 Tal J, Schliamser L M, Leibovitz Z, Ohel G, Attias D. A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure.  Hum Reprod . 1999;  14 1624-1627
• 46 Strickland S, Reich E, Sherman M I. Plasminogen activator in early embryogenesis: enzyme production by trophoblast and parietal endoderm.  Cell . 1976;  9 231
• 47 Sappino A P, Huarte J, Belin D. Plasminogen activators in tissue remodelling and invasion: mRNA localization in mouse ovaries and implanting embryos.  J Cell Biol . 1989;  109 2471
• 48 Hoffman G E, Glatstein I, Schatz F. Immunohistochemical localization of urokinase type plasminogen activator and plasminogen activator inhibitors 1 and 2 in early human implantation sites.  Am J Obstet Gynecol . 1994;  170 671
• 49 van Pampus G M, Dekker G A, Wolf H. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia.  Am J Obstet Gynecol . 1999;  180 1146-1150
• 50 Lindoff C, Ingemarsson I, Martinsson G, Segelmark M, Thysell H, Astedt B. Preeclampsia is associated with a reduced response to activated protein C.  Am J Obstet Gynecol . 1997;  176 457-460
• 51 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
• 52 Sanson B-J, Freiderich P W, Simioni P. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women.  Thromb Haemost . 1996;  75 387-388
• 53 Sibai B M. Thrombophilias and adverse outcomes of pregnancy: what should a clinician do?.  N Engl J Med . 1999;  340 50-52
• 54 De Stefano V, Martinelli I, Mannucci P M. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.  N Engl J Med . 1999;  341 801-806
• 55 Balasch J, Reverter J C, Fabregues F. First-trimester repeated abortion is not associated with activated protein C resistance.  Hum Reprod . 1997;  12 1094-1097
• 56 Brenner B, Mandel H, Lanir N. Activated protein C resistance can be associated with recurrent fetal loss.  Br J Haematol . 1997;  97 551-554
• 57 Grandone E, Margaglione M, Colaizzo D. Factor V Leiden is associated withr epeated and recurrent unexplained fetal losses.  Thromb Haemost . 1997;  77 822-824
• 58 Dizon-Townson D S, Kinney S, Branch D W, Ward K. The factor V Leiden mutation is not a common cause of recurrent miscarriage.  J Reprod Immunol . 1997;  34 217-223
• 59 Metz J, Kloss M, O'Malley C J. Prevalence of factor V Leiden is not increased in women with recurrent miscarriage.  Clin Appl Thromb Hemost . 1997;  3 137-140
• 60 Ridker P M, Miletich J P, Buring J E. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss.  Ann Intern Med . 1998;  128 1000-1003
• 61 Kutteh W H, Park V M, Deitcher S R. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss.  Fertil Steril . 1998;  71 1048-1053
• 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 6-9
• 63 Souza S S, Ferriani R A, Pontes A G, Zago M A, Franco R F. Factor V Leiden and factor II G20210A mutations in patients with recurrent abortion.  Hum Reprod . 1999;  14 2448-2450
• 64 Holmes Z R, Regan L, Chilcott I, Cohen H. The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss.  Br J Haematol . 1999;  105 98-101