Download PDF
Thromb Haemost 2004; 91(02): 290-295
DOI: 10.1160/TH03-09-0596
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Maternal thrombophilias are not associated with early pregnancy loss

Henry Roqué
1   Department of Obstetrics and Gynecology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
,
Michael J. Paidas
2   Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
,
Edmund F. Funai
2   Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
,
Edward Kuczynski
2   Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
,
Charles J. Lockwood
2   Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, USA
› Author AffiliationsGrant support: This work was supported in part by a grant from the National Institutes of Health RO1 HL070004-01A1 (CJL).
Further Information

Publication History

Received 24 September 2003

Accepted after resubmission 03 January 2003

Publication Date:
01 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

We investigated the association between inherited and acquired maternal thrombophilias and adverse pregnancy events. A cohort of 491 patients with a history of adverse pregnancy outcomes was evaluated for activated protein C resistance, factor V Leiden and prothrombin G20210A mutations, hyperhomocysteinemia, deficiencies of antithrombin, protein C and S and both anticardiolipin antibodies and lupus anticoagulants. The study had an 80% power to detect a 15% difference in the prevalence of thrombophilia for 1st trimester loss. In our high-risk cohort the presence of 1 maternal thrombophilia or more than one thrombophilia were found to be protective of recurrent losses at < 10 weeks (1 thrombophilia: OR: 0.55, 95% CI: 0.33–0.92; >1 thrombophilia: OR: 0.48, 95%CI:0.29–0.78). In contrast, the presence of maternal thrombophilia(s) was modestly associated with an increased risk of losses ≥ 10 weeks (1 thrombophilia: OR:1.76, 95%CI: 1.05–2.94, >1 thrombophilia: OR:1.66, 95%CI:1.03–2.68). Women who experienced only euploid losses were not more likely to have an identified thrombophilia than women who experienced only aneuploid losses (OR 1.03; 0.38–2.75). The presence of maternal thrombophilia was associated with an increased risk of fetal loss after 14 weeks, fetal growth restriction, abruption and preeclampsia. There was a significant “dose-dependent” increase in the risk of abruption (OR:3.60, 95%CI: 1.43–9.09) and preeclampsia (OR:3.21, 95%CI:1.20–8.58). In conclusion, these data indicate maternal thrombophilias are not associated with pregnancy wastage prior to 10 weeks of gestation.

Keywords

Maternal thrombophilia - recurrent abortion - fetal loss
 

  • References

  • 1 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 Study5 (NOHA5). Thromb Haemost 1999; 81 (06) 891-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Girling J, de Swiet M. Inherited thrombophilia and pregnancy. Curr Opin Obstet Gynecol 1998; 10 (02) 135-44.
    CrossrefPubMedGoogle Scholar
  • 3 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 (01) 9-13.
    CrossrefPubMedGoogle Scholar
  • 4 Lockwood CJ, Rand JH. The immunobiology and obstetrical consequences of antiphospholipid antibodies. Obstet Gynecol Surv 1994; 49 (06) 432-41.
    CrossrefPubMedGoogle Scholar
  • 5 Lockwood CJ. Inherited thrombophilias in pregnant patients. Prenatal and Neonatal Medicine 2001; 06: 3-14.
    PubMedGoogle Scholar
  • 6 Brenner B. Inherited thrombophilia and pregnancy loss. Thromb Haemost 1999; 82 (02) 634-40.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Foka ZJ, Lambropoulos AF, Saravelos H. et al.. Factor V leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod 2000; 15 (02) 458-62.
    CrossrefPubMedGoogle Scholar
  • 8 Hatzis T, Cardamakis E, Drivalas E. et al.. Increased resistance to activated protein C and factor V Leiden in recurrent abortions. Review of other hypercoagulability factors. Eur J Contracept Reprod Health Care 1999; 04 (03) 135-44.
    CrossrefPubMedGoogle Scholar
  • 9 Kutteh WH, Park VM, Deitcher SR. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999; 71 (06) 1048-53.
    CrossrefPubMedGoogle Scholar
  • 10 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 (09) 736-9.
    CrossrefPubMedGoogle Scholar
  • 11 Murphy RP, Donoghue C, Nallen RJ. et al.. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 2000; 20 (01) 266-70.
    CrossrefPubMedGoogle Scholar
  • 12 Ozcan T, Rinder HM, Murphy J. et al.. Genetic thrombophilia mutations are not increased in patients with recurrent losses. Obstet Gynecol 2001; 97 (04) (Suppl. 01) S31.
    PubMedGoogle Scholar
  • 13 Pihusch R, Buchholz T, Lohse P. et al.. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 2001; 46 (02) 124-31.
    CrossrefPubMedGoogle Scholar
  • 14 Preston FE, Rosendaal FR, Walker ID. et al.. Increased fetal loss in women with heritable thrombophilia [see comments]. Lancet 1996; 348 9032 913-6.
    CrossrefPubMedGoogle Scholar
  • 15 Rai R, Shlebak A, Cohen H. et al.. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16 (05) 961-5.
    CrossrefPubMedGoogle Scholar
  • 16 Ridker PM, Miletich JP, Buring JE. et al.. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998; 128 12 Pt 1: 1000-3.
    CrossrefPubMedGoogle Scholar
  • 17 Roqué H, Paidas M, Rebarber A. et al.. There is no association between maternal thrombophilia and recurrent first trimester loss. Am J Obstet Gynecol 2001; 184 (01) s15.
    PubMedGoogle Scholar
  • 18 Souza SS, Ferriani RA, Pontes AG. et al.. Factor V leiden and factor II G20210A mutations in patients with recurrent abortion. Hum Reprod 1999; 14 (10) 2448-50.
    CrossrefPubMedGoogle Scholar
  • 19 Tal J, Schliamser LM, Leibovitz Z. et al.. A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure. Hum Reprod 1999; 14 (06) 1624-7.
    CrossrefPubMedGoogle Scholar
  • 20 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 (01) 31-5.
    CrossrefPubMedGoogle Scholar
  • 21 Younis JS. Thrombophilia and recurrent fetal loss-related?. Fertil Steril 2000; 73 (03) 652-4.
    PubMedGoogle Scholar
  • 22 Rey E, Kahn SR, David M. et al.. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361 9361: 901-8.
    CrossrefPubMedGoogle Scholar
  • 23 Burton GJ, Jauniaux E, Watson AL. 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 (03) 718-24.
    Google Scholar
  • 24 Jaffe R. Investigation of abnormal first-trimester gestations by color Doppler imaging. J Clin Ultrasound 1993; 21 (08) 521-6.
    CrossrefPubMedGoogle Scholar
  • 25 Rodesch F, Simon P, Donner C. et al.. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol 1992; 80 (02) 283-5.
    PubMedGoogle Scholar
  • 26 Starzyk KA, Pijnenborg R, Salafia CM. Decidual and vascular pathophysiology in pregnancy compromise. Semin Reprod Endocrinol 1999; 17 (01) 63-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Rodesch F, Simon P, Donner C. et al.. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol 1992; 80 (02) 283-5.
    PubMedGoogle Scholar
  • 28 Salafia CM, Pezzullo JC, Lopez-Zeno JA. et al.. Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol 1995; 173 (04) 1097-105.
    CrossrefPubMedGoogle Scholar
  • 29 Salafia CM, Parke AL. Placental pathology in systemic lupus erythematosus and phospholipid antibody syndrome. Rheum Dis Clin North Am 1997; 23 (01) 85-97.
    CrossrefPubMedGoogle Scholar
  • 30 Salafia CM. Placental pathology of fetal growth restriction. Clin Obstet Gynecol 1997; 40 (04) 740-9.
    CrossrefPubMedGoogle Scholar
  • 31 Arias F, Romero R, Joist H. et al.. Thrombophilia: a mechanism of disease in women with adverse pregnancy outcome and thrombotic lesions in the placenta. J Matern Fetal Med 1998; 07 (06) 277-86.
    PubMedGoogle Scholar
  • 32 Gomez E, van der Poel SC, Jansen JH. et al.. Rapid simultaneous screening of factor V Leiden and G20210A prothrombin variant by multiplex polymerase chain reaction on whole blood. Blood 1998; 91 (06) 2208-9.
    PubMedGoogle Scholar
  • 33 Kirschbaum NE, Foster PA. The polymerase chain reaction with sequence specific primers for the detection of the factor V mutation associated with activated protein C resistance. Thromb Haemost 1995; 74 (03) 874-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Frantzen F, Faaren AL, Alfheim I. et al.. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum. Clin Chem 1998; 44 (02) 311-6.
    PubMedGoogle Scholar
  • 35 Sturk A, Morrien-Salomons WM, Huisman MV. et al.. Analytical and clinical evaluation of commercial protein C assays. Clin Chim Acta 1987; 165 2-3 263-70.
    CrossrefPubMedGoogle Scholar
  • 36 Vigano SD'Angelo, Comp PC, Esmon CT. et al.. Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. J Clin Invest 1986; 77 (02) 416-25.
    CrossrefPubMedGoogle Scholar
  • 37 Fernandez JA, Estelles A, Gilabert J. et al.. Functional and immunologic protein S in normal pregnant women and in full-term newborns. Thromb Haemost 1989; 61 (03) 474-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Andrew M, Paes B, Milner R. et al.. Development of the human coagulation system in the full-term infant. Blood 1987; 70 (01) 165-72.
    PubMedGoogle Scholar
  • 39 Messmore H, Fareed J, Kniffin J. et al.. Synthetic substrate assays of the coagulation enzymes and their inhibitors. Comparison with clotting and immunologic methods for clinical and experimental usage. Ann N Y Acad Sci 1981; 370: 785-97.
    PubMedGoogle Scholar
  • 40 Harris EN, Gharavi AE, Patel SP. et al.. Evaluation of the anti-cardiolipin antibody test: report of an international workshop held 4 April 1986. Clin Exp Immunol 1987; 68 (01) 215-22.
    PubMedGoogle Scholar
  • 41 Pierangeli SS, Vigo-Pelfrey C, Harris EN. Comparison of a fluorometric test with the standard ELISA assay for the detection of anticardiolipin antibodies. Clin Exp Rheumatol 1993; 11 (03) 349-50.
    PubMedGoogle Scholar
  • 42 Triplett DA, Brandt JT, Kaczor D. et al.. Laboratory diagnosis of lupus inhibitors: a comparison of the tissue thromboplastin inhibition procedure with a new platelet neutralization procedure. Am J Clin Pathol 1983; 79 (06) 678-82.
    CrossrefPubMedGoogle Scholar
  • 43 Doubilet PM, Benson CB, Nadel AS. et al.. Improved birth weight table for neonates developed from gestations dated by early ultrasonography. J Ultrasound Med 1997; 16 (04) 241-9.
    CrossrefPubMedGoogle Scholar
  • 44 Gordon SLJD. Recurrent early pregnancy losses. In: Handbook for Clinical Gynecologic Endocrinology and Infertility. New York: Lippincott Williams & Wilkins; 2002: 440-7.
    Google Scholar
  • 45 Alfirevic SKZ, Brigham S. Amniocentesis and chorionic villus sampling for prenatal diagnosis. Cochrane Database Syst Rev 2003; 03: cd003252.
    PubMedGoogle Scholar
  • 46 Management of recurrent early pregnancy loss. ACOG Practice Bulletin 2001; 24.
    PubMed
  • 47 Gopel W, Ludwig M, Junge AK. et al.. Selection pressure for the factor-V-Leiden mutation and embryo implantation. Lancet 2001; 358 9289 1238-9.
    CrossrefPubMedGoogle Scholar
  • 48 Watson AL, Skepper JN, Jauniaux E. et al.. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab 1998; 83 (05) 1697-705.
    PubMedGoogle Scholar
  • 49 Clark P, Brennand J, Conkie JA. et al.. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79 (06) 1166-70.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Bonnar J, Green R, Norris L. Inherited thrombophilia and pregnancy: the obstetric perspective. Semin Thromb Hemost 1998; 24 Suppl: (Suppl. 01) 49-53.
    PubMedGoogle Scholar
  • 51 Clark P, Walker ID, Greer I. Acquired activated protein-C resistance in pregnancy and association with increased thrombin generation and fetal weight [letter] [see comments]. Lancet 1999; 353 9149 292-3.
    PubMedGoogle Scholar