Download PDF
Am J Perinatol 2006; 23(8): 499-506
DOI: 10.1055/s-2006-954961
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Thrombophilia and Adverse Maternal-Perinatal Outcome: Controversies in Screening and Management

Caroline L. Stella1 , Helen Y. How1 , Baha M. Sibai1
  • 1University of Cincinnati College of Medicine, Division of Maternal-Fetal Medicine, Cincinnati, Ohio
Further Information

Publication History

Publication Date:
08 November 2006 (online)

    Permissions and Reprints

ABSTRACT

A recent review of the literature on thrombophilia and adverse pregnancy outcome reveals contradictory findings. There are retrospective and prospective studies that recommend testing for genetic and acquired markers of thrombophilia for those with the enumerated adverse pregnancy outcome. Based on our review, routine screening for thrombophilias in women with a history of adverse pregnancy outcome (preeclampsia, abruptio placenta, intrauterine growth restriction, and fetal loss) is not justified. Based on data from observational studies and few randomized trials with inadequate number of subjects, there is consensus that women with true antiphospholipid antibody syndrome should receive low-dose aspirin plus adjusted-dose heparin in subsequent pregnancies. Some authors also recommend heparin prophylaxis in subsequent pregnancies in women with genetic thrombophilia with previous adverse pregnancy outcome. However, this recommendation is not based on randomized trials. Hence, a randomized double-blind, controlled trial is urgently needed to evaluate the benefit of heparin during pregnancy in women with a history of adverse pregnancy outcome in association with genetic thrombophilia.

KEYWORDS

Thrombophilia - adverse pregnancy outcome

REFERENCES

  • 1 Paidas M J, De-Hui W K, Arkel Y S. Screening and management of inherited thrombophilias in the setting of adverse pregnancy outcome.  Clin Perinatol. 2004;  31 783-805
    CrossrefPubMedGoogle Scholar
  • 2 Barbour L A. Thromboembolism in pregnancy. ACOG Committee in Obstetric Practice Bulletin. Number 19. Washington, DC; The College 2000
    Google Scholar
  • 3 Rey E, Kahn S R, David M, Shrier I. Thrombophilic disorders and fetal loss: a metaanalysis.  Lancet. 2003;  361 901-908
    CrossrefPubMedGoogle Scholar
  • 4 Ridker P M, Miletich J P, Hennekens C H, Burring J E. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening.  JAMA. 1997;  277 1305-1307
    CrossrefPubMedGoogle Scholar
  • 5 Dizon-Townson D, Miller C, Sibai B et al.. The relationship of factor V Leiden mutation and pregnancy outcomes for mother and fetus.  Obstet Gynecol. 2005;  106 517-524
    CrossrefPubMedGoogle Scholar
  • 6 Lockwood C J. Inherited thrombophilias in pregnant patients.  Prenat Neonat Med. 2001;  6 3-14
    PubMedGoogle Scholar
  • 7 Greer I A. Thrombophilia: implications for pregnancy outcome.  Thromb Res. 2003;  109 73-81
    CrossrefPubMedGoogle Scholar
  • 8 Rosendaal F R. Venous thrombosis: a multicausal disease.  Lancet. 1999;  353 1167-1173
    CrossrefPubMedGoogle Scholar
  • 9 Lee R M, Brown M A, Branch D W, Ward K, Silver R M. Anticardiolipin and anti- B2 glycoprotein-I antibodies in preeclampsia.  Obstet Gynecol. 2003;  102 294-300
    CrossrefPubMedGoogle Scholar
  • 10 Kujovich J L. Thrombophilia and pregnancy complications.  Am J Obstet Gynecol. 2004;  191 412-424
    CrossrefPubMedGoogle Scholar
  • 11 Lin L, August P. Genetic thrombophilias and preeclampsia: a meta-analysis.  Obstet Gynecol. 2005;  105 182-192
    CrossrefPubMedGoogle Scholar
  • 12 Mignini L E, Latthe P M, Villar J, Killy M D, Carroli G, Khan K S. Mapping the theories of preeclampsia: the role of homocysteine.  Obstet Gynecol. 2005;  105 411-425
    PubMedGoogle Scholar
  • 13 Ananth C V. Placental abruption and perinatal mortality in the United States.  Am J Epidemiol. 2001;  153 332-337
    CrossrefPubMedGoogle Scholar
  • 14 Branch D W, Porter T F, Rittenhouse L et al.. Antiphospholipid antibodies in women at risk for preeclampsia.  Am J Obstet Gynecol. 2001;  184 825-834
    CrossrefPubMedGoogle Scholar
  • 15 Dreyfus M, Hedelin G, Kutnahorsky R et al.. Antiphospholipid antibodies and preeclampsia: a case-control study.  Obstet Gynecol. 2001;  97 29-34
    CrossrefPubMedGoogle Scholar
  • 16 Lee R M, Brown M A, Branch D W, Ward K, Silver R M. Anticardiolipin and anti-β2-glycoprotein-1 antibodies in preeclampsia.  Obstet Gynecol. 2003;  102 294-300
    CrossrefPubMedGoogle Scholar
  • 17 Esplin M S. Antiphospholipid syndrome. ACOG Practice Bulletin No. 68.  Obstet Gynecol. 2005;  106 1113-1121
    PubMedGoogle Scholar
  • 18 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 1042-1048
    CrossrefPubMedGoogle Scholar
  • 19 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;  175 902-905
    CrossrefPubMedGoogle Scholar
  • 20 Riyazi N, Leeda M, de Vries J IP, Huijgens P C, van Geijn H P, Dekker G A. Low molecular weight heparin combines with aspirin in pregnant women with thrombophilia and a history of preeclampsia or fetal growth restriction: a preliminary study.  Eur J Obstet Gynecol Reprod Biol. 1998;  80 49-54
    CrossrefPubMedGoogle Scholar
  • 21 Nagy B, Toth T, Rigo Jr J, Karadi I, Romics L, Papp Z. Detection of factor V Leiden mutation in severe preeclamptic Hungarian women.  Clin Genet. 1998;  53 478-481
    CrossrefPubMedGoogle Scholar
  • 22 Krauss T, Augustin H G, Osmers R, Meden H, Unterhalt M, Kuhn W. Activated protein C resistance and factor V Leiden in patients with hemolysis, elevated liver enzymes, low platelets syndrome.  Obstet Gynecol. 1998;  92 457-460
    CrossrefPubMedGoogle Scholar
  • 23 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 9-13
    CrossrefPubMedGoogle Scholar
  • 24 van Pampus E C, Dekker G A, Wolf H et al.. High prevalence of hemostatic abnormalities in women with a history of severe preeclampsia.  Am J Obstet Gynecol. 1999;  180 1146-1150
    CrossrefPubMedGoogle Scholar
  • 25 DeGroot C J, Bloemankamp K W, Duvekot E J et al.. Preeclampsia and genetic factors for thrombosis: a case control study.  Am J Obstet Gynecol. 1999;  181 975-980
    CrossrefPubMedGoogle Scholar
  • 26 Kupferminc M J, Fait G, Many A, Girdon D, Eldor A, Lessing J B. Severe preeclampsia: high frequency of genetic thrombophilic mutations.  Obstet Gynecol. 2000;  96 45-49
    CrossrefPubMedGoogle Scholar
  • 27 Rigo J, Nagy B, Fintor L, Tanyi J, Beke A, Karadi I, Papp Z. Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutations and 5,10 methylenetetrahydrofolate reductase.  Hypertens Pregnancy. 2000;  19 163-172
    CrossrefPubMedGoogle Scholar
  • 28 von Tempelhoff G F. Incidence of factor V Leiden mutation, coagulation inhibitor deficiency, and elevated antiphospholipid-antibodies in patients with preeclampsia or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets).  Thromb Res. 2000;  100 363-365
    CrossrefPubMedGoogle Scholar
  • 29 Kupferminc M J, Peri H, Zwang E, Yaron Y, Wolman I, Eldor A. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss.  Acta Obstet Gynecol Scand. 2000;  79 963-967
    CrossrefPubMedGoogle Scholar
  • 30 Kim Y J, Williamson R A, Murray J C et al.. Genetic susceptibility to preeclampsia: roles of cytosine-to-thymine substitution at nucleotide 677 of the gene for methytetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathione [beta]-synthase, and factor V Leiden mutation.  Am J Obstet Gynecol. 2001;  184 1211-1217
    CrossrefPubMedGoogle Scholar
  • 31 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;  185 153-157
    CrossrefPubMedGoogle Scholar
  • 32 Currie L, Peek M, McNiven M, Prosser I, Mansour J, Ridgway J. Is there an increased maternal-infant prevalence of factor V Leiden in association with severe pre-eclampsia?.  BJOG. 2002;  109 191-196
    PubMedGoogle Scholar
  • 33 Benedetto C, Marozio L, Salton L, Maula V, Chieppa G, Massobrio M. Factor V Leiden and factor II G20210A in preeclampsia and HELLP syndrome.  Acta Obstet Gynecol Scand. 2002;  81 1095-1100
    CrossrefPubMedGoogle Scholar
  • 34 Schlembach D, Beinder E, Zingsem J, Wunsiedler U, Beckmann M W, Fischer T. Association of maternal and/or fetal factor V Leiden and G20210A prothrombin mutation with HELLP syndrome and intrauterine growth restriction.  Clin Sci. 2003;  105 279-285
    CrossrefPubMedGoogle Scholar
  • 35 Mello G, Parretti E, Marozio L et al.. Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study.  Hypertension. 2005;  46 1270-1274
    CrossrefPubMedGoogle Scholar
  • 36 Stanley-Christian H, Ghidini A, Sacher R, Shemirani M. Fetal genotype for specific inherited thrombophilias is not associated with severe preeclampsia.  J Soc Gynecol Investig. 2005;  12 198-201
    PubMedGoogle Scholar
  • 37 Prochaska M, Happach C, Marsal K, Dahlback B, Lindqvist P G. Factor V Leiden in pregnancies complicated by placental abruption.  Br J Obstet Gynaecol. 2003;  110 462-466
    PubMedGoogle Scholar
  • 38 Hira B, Pegoraro R J, Rom L, Govender T, Moodley J. Polymorphisms in various coagulation genes in black South African women with placental abruption.  BJOG. 2002;  109 574-575
    PubMedGoogle Scholar
  • 39 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 35-44
    CrossrefPubMedGoogle Scholar
  • 40 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 19-25
    CrossrefPubMedGoogle Scholar
  • 41 Verspyck E, Borg J Y, Le Cam-Duchez V et al.. Thrombophilia and fetal growth restriction.  Eur J Obstet Gynecol Reprod Biol. 2004;  113 36-40
    CrossrefPubMedGoogle Scholar
  • 42 McCowan L ME, Craigie R M, 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;  188 981-992
    CrossrefPubMedGoogle Scholar
  • 43 Kupferminc M J, Many A, Bar-Am A, Lessing J B, Ascher-Landsberg J. Mid-trimester severe intrauterine growth restriction is associated with high prevalence of thrombophilia.  BJOG. 2002;  109 1373-1376
    PubMedGoogle Scholar
  • 44 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;  192 694-708
    CrossrefPubMedGoogle Scholar
  • 45 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 1015-1018
    CrossrefPubMedGoogle Scholar
  • 46 Gonen R, Lavi N, Attias D et al.. Absence of association of inherited thrombophilia with unexplained third-trimester intrauterine fetal death.  Am J Obstet Gynecol. 2005;  192 742-746
    CrossrefPubMedGoogle Scholar
  • 47 Many A, Elad R, Yaron Y, Eldor A, Lessing J, Kupferminc M J. Third-trimester unexplained intrauterine fetal death is associated with inherited thrombophilia.  Obstet Gynecol. 2002;  99 684-687
    CrossrefPubMedGoogle Scholar
  • 48 Hefler L, Jirecek S, Heim K et al.. Genetic polymorphisms associated with thrombophilia and vascular disease in women with unexplained late intrauterine fetal death: a multicenter study.  J Soc Gynecol Investig. 2004;  11 42-44
    PubMedGoogle Scholar
  • 49 Sibai B M, El-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primagravid women: subsequent pregnancy outcome and remote prognosis.  Am J Obstet Gynecol. 1986;  155 1011-1016
    CrossrefPubMedGoogle Scholar
  • 50 Sibai B M, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis.  Am J Obstet Gynecol. 1991;  165 1408-1412
    CrossrefPubMedGoogle Scholar
  • 51 Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis J S. Gestational outcome in thrombophilix women with recurrent pregnancy loss treated with enoxaparin.  Thromb Haemost. 2000;  83 693-697
    PubMedGoogle Scholar
  • 52 Ogueh O, Chen M F, Spurll G, Benjamin A. Outcome of pregnancy in women with hereditary thrombophilia.  Int J Gynaecol Obstet. 2001;  74 247-253
    CrossrefPubMedGoogle Scholar
  • 53 Grandone E, Brancaccio V, Colaizzo D et al.. Preventing adverse obstetric outcomes in women with genetic thrombophilia.  Fertil Steril. 2002;  78 371-375
    CrossrefPubMedGoogle Scholar
  • 54 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
    CrossrefPubMedGoogle Scholar
  • 55 Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipids antibodies (or antiphospholipid antibodies).  BMJ. 1997;  314 253-257
    CrossrefPubMedGoogle Scholar
  • 56 Silver R K, MacGregor S N, Sholl J S, Hobart J M, Neerhof M G, Ragin A. Comparative trial of prednisone versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients.  Am J Obstet Gynecol. 1993;  169 1411-1417
    PubMedGoogle Scholar
  • 57 Pattison N S, Chamley L W, Birdsall M, Zanderigo A M, Liddell H S, McDougall J. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial.  Am J Obstet Gynecol. 2000;  183 1008-1012
    CrossrefPubMedGoogle Scholar
  • 58 Farquharson R G, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.  Obstet Gynecol. 2002;  100 408-413
    CrossrefPubMedGoogle Scholar
  • 59 Gris J C, Mercier E, Quere I et al.. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.  Blood. 2004;  103 3695-3699
    CrossrefPubMedGoogle Scholar
  • 60 Branch D W, Khamashta M A. Antiphospholipid syndrome: obstetric diagnosis, management and controversies.  Obstet Gynecol. 2003;  101 1333-1344
    CrossrefPubMedGoogle Scholar
  • 61 Rotmensch S, Liberati M, Mittleman M, Ben Rafael Z. Activated protein C resistance and adverse pregnancy outcome.  Am J Obstet Gynecol. 1997;  177 170-173
    PubMedGoogle Scholar
  • 62 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 of fetal growth restriction.  Am J Obstet Gynecol. 1998;  179 135-139
    CrossrefPubMedGoogle Scholar

Caroline L StellaM.D. 

Maternal-Fetal Medicine Fellow, Clinical Instructor, Division of Maternal-Fetal Medicine, University of Cincinnati

231 Albert Sabin Way, Room 5052, Medical Sciences Building, P.O. Box 670526, Cincinnati, OH 45267-0526

      >