Advertisement

Archives of Gynecology and Obstetrics

, Volume 291, Issue 3, pp 671–679 | Cite as

Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association

  • C. SergiEmail author
  • T. Al Jishi
  • M. Walker
Gynecologic Endocrinology and Reproductive Medicine

Abstract

Background

Recently, the interest has focused on the increased prevalence of thrombophilic defects in women with gestational complications.

Objective

To explore whether women with early recurrent pregnancy loss (RPL) are at increased risk of being carriers of the Factor V Leiden (FVL) mutation compared to those who have a normal reproductive history.

Methods

A manual and electronic literature search was undertaken to identify studies with a case–control population of women with two or more first trimester RPLs of undetermined origin and age- and ethnicity-matched control group with normal reproductive history and at least one full-term delivery. Both groups were screened for FVL mutation. A quality assessment was performed according to the pre-established validity criteria and using the Cochrane handbook guidelines for observational studies. The combinability of studies was assessed by clinical and statistical methods (Breslow–Day’s test of homogeneity). Quantitative data were abstracted with regard to the prevalence of FVL mutation in the case and control group, and 2 × 2 tables were created. The ratio comparing the odds of FVL mutation in women with early RPL with the odds of FVL mutation in women with normal reproductive outcome was calculated with its 95 % confidence interval (CI) by Mantel–Haenszel method.

Results

Nine studies met the inclusion criteria and were selected for review. A total of 2,147 women were screened for the FVL mutation, 1,305 women with early RPL, and 842 women with no gestational complications. Women with early RPL had indeed a statistically significantly increased carrier frequency of FVL mutation, the common OR being 1.68 (95 % CI: 1.16–2.44).

Conclusion

FVL carrier state may increase the susceptibility for early RPL. Testing for FVL mutation should be considered in women with unexplained early RPL and thrombophylaxis has been suggested in women with unexplained RPL associated with FVL mutation.

Keywords

Factor V Leiden Recurrent pregnancy loss Recurrent spontaneous abortions First trimester Thrombophilia Coagulation defects 

Abbreviations

FVL

Factor V Leiden

RPL

Recurrent pregnancy loss

APC

Activated protein C

Notes

Acknowledgements

CS re-addressed specific questions, discussed in detail data, analysis, and results, and wrote the final draft of the manuscript. TAJ conceived the study, designed the study, analyzed data and results, and wrote the first draft of the manuscript. MW conceived the study and reviewed the paper. We are very grateful to the Saudi Cultural Bureau, Ottawa, ON, for the support of Dr. Al-Jishi.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The manuscript does not contain clinical studies or patient data.

References

  1. 1.
    Younis JS, Ohel G, Brenner B, Ben-Ami M (1997) Familial thrombophilia—the scientific rationale for thrombophylaxis in recurrent pregnancy loss? Hum Reprod 12:1389–1390PubMedCrossRefGoogle Scholar
  2. 2.
    Cook CL, Pridham DD (1995) Recurrent pregnancy loss. Curr Opin Obstet Gynecol 7:357–366PubMedCrossRefGoogle Scholar
  3. 3.
    Clifford K, Rai R, Watson H, Regan L (1994) An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 9:1328–1332PubMedGoogle Scholar
  4. 4.
    Kutteh WH, Park VM, Deitscher SR (1999) Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 71:1048–1053PubMedCrossRefGoogle Scholar
  5. 5.
    Haywood L, Brown MD (1991) Antiphospholipid antibodies and recurrent pregnancy loss. Clin Obstet Gynecol 34:1–17CrossRefGoogle Scholar
  6. 6.
    Blumenfeld Z, Weiner Z, Lorber M, Sujov P, Thaler I (1991) Anticardiolipin antibodies in patients with recurrent pregnancy wastage: treatment and uterine blood flow. Obstet Gynecol 78:584–589PubMedGoogle Scholar
  7. 7.
    Kamashta MA (1998) Management of thrombosis and pregnancy loss in the antiphospholipid syndrome. Lupus 7(Suppl 2):S162–S165CrossRefGoogle Scholar
  8. 8.
    Sanson BJ, Friederich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A (1996) The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost 75:387–388PubMedGoogle Scholar
  9. 9.
    Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J (1996) Increased fetal loss in women with heritable thrombophilia. Lancet 348:913–916PubMedCrossRefGoogle Scholar
  10. 10.
    Meinardi JR, Middeldorp S, Kam PJ, Koopman MMW, van Pampus ECM, Hamulyak K (1999) Increased risk of fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 130:736–739PubMedCrossRefGoogle Scholar
  11. 11.
    Tormen D, Simioni P, Prandoni P, Luni S, Innella B, Sabbion P et al (1999) The risk of fetal loss in family members of probands with factor V Leiden mutation. Thromb Hamost 82:1237–1239Google Scholar
  12. 12.
    Dahlback B, Carlsson M, Svensoon PJ (1993) Familial thrombophilia due to a previously recognized mechanism characterised by poor anticoagulant response to activated protein C. Proc Natl Acad Sci 90:1004–1008PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Bertina RM, Koeleman BPC, Koster T (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369:64–67PubMedCrossRefGoogle Scholar
  14. 14.
    Dahlback B (1995) Molecular genetics of thrombophilia factor V gene mutation causing resistance to activated protein C as a basis of the hypercoagulable state. J Clin Lab Med 125:566–571Google Scholar
  15. 15.
    Dahlback B (1994) Physiological anticoagulation: resistance activated protein C and venous thromboembolism. J Clin Invest 94:923–927PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Zivelin A, Griffin JH, Xu X, Pabinger I, Samama M, Conrad J et al (1997) A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 89:397–402PubMedGoogle Scholar
  17. 17.
    Rees DC, Cox M, Clegg JB (1995) World distribution of factor V Leiden. Lancet 346:1133–1134PubMedCrossRefGoogle Scholar
  18. 18.
    Chan LC, Bourke C, Lam CK, Liu HW, Brookes S, Jenkins Y et al (1996) Lack of activated protein C resistance in healthy Hong Kong Chinese blood donors: correlation with absence of Arg 506-Gln mutation of factor V gene. Thromb Haemost 75:522–523PubMedGoogle Scholar
  19. 19.
    Griffin JH, Evart B, Wideman C, Fernandez JA (1993) Antocoagulant protein C pathway defective in majority of thrombophilic patients. Blood 82:1989–1994PubMedGoogle Scholar
  20. 20.
    Svensson PJ, Dahlback B (1994) Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 330:517–522PubMedCrossRefGoogle Scholar
  21. 21.
    Hellgren M, Svensson PJ, Dahlback B (1995) Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol 173:210–213PubMedCrossRefGoogle Scholar
  22. 22.
    Vanderbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR (1994) Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leide mutation. Lancet 344:1453–1457CrossRefGoogle Scholar
  23. 23.
    Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA 283:2008–2012PubMedCrossRefGoogle Scholar
  24. 24.
    Khan K, Riet GT, Glanville J et al (2000) Undertaking systematic reviews of research on effectiveness. CRD’s guidance for carrying out or commissioning reviews, 2nd edn. NHS Centre for Reviews and Dissemination, University of York, YorkGoogle Scholar
  25. 25.
    Formulating the problem. In: Alderson P, Green S, Higgins JPT (eds) [Cochrane Reviewer’s Handbook 4.2.2 ed]. Available at http://www.cochrane.org/resources/handbook/hbook.htm
  26. 26.
    Zoller B, Sevensson PJ, He X, Dahlback B (1994) Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 94:2521–2524PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Ridger PM, Miletich JP, Buring JE (1997) Ethnic distribution of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening. J Am Med Assoc 277:1305–1307CrossRefGoogle Scholar
  28. 28.
    Bauer KA (1995) Management of patients with hereditary defects predisposing to thrombosis including pregnant women. Throm Haemost 74:94–100Google Scholar
  29. 29.
    Pihusch R, Buchholz T, Lohse P, Rubsamen H, Rogenhofer N, Hasbargen U, Hiller E, Thaler C (2001) Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol 46:124–131PubMedCrossRefGoogle Scholar
  30. 30.
    Rai R, Regan L, Hadley E (1996) Second trimester pregnancy loss is associated with activate C resistance. Br J Haematol 92:489–490PubMedGoogle Scholar
  31. 31.
    Brenner B, Mandel H, Lanir N, Younis J, Rothbart H, Ohel G et al (1997) Activated protein C resistance can be associated with recurrent pregnancy loss. Br J Haematol 97:551–554PubMedCrossRefGoogle Scholar
  32. 32.
    Metz J, Kloss M, O’ Malley CJ et al (1997) Prevalence of Factor V Leiden is not increased in women with recurrent miscarriage. Clin Appl Thromb Hemost 3:137–140CrossRefGoogle Scholar
  33. 33.
    Ridker PM, Miletich JP, Buring JE, Ariyo A et al (1998) Factor V Leiden as a risk factor for recurrent pregnancy loss. Ann Intern Med 128:1000–1003PubMedCrossRefGoogle Scholar
  34. 34.
    Souza SS, Ferriani RA, Pontes AG, Zago MA, Franco RF (1999) Factor V Leiden and factor II G20210A mutations in patients with recurrent abortion. Hum Reprod 14(10):2448–2450PubMedCrossRefGoogle Scholar
  35. 35.
    Tal J, Schliamser LM, Leibovitz Z, Ohel G, Attias D (1999) A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure. Hum Reprod 14(6):1624–1627PubMedCrossRefGoogle Scholar
  36. 36.
    Wramsby ML, Sten-Linder M, Bremme K (2000) Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Steril 74(5):987–991PubMedCrossRefGoogle Scholar
  37. 37.
    Sarig G, Younis JS, Hoffman R, Lanir N, Blumenfeld Z, Brenner B (2002) Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 77(2):342–347PubMedCrossRefGoogle Scholar
  38. 38.
    Younis JS, Ohel G, Brenner B, Haddad S, Lanir N, Ben-Ami M (2000) The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation. Br J Obst Gyn 107:415–419CrossRefGoogle Scholar
  39. 39.
    Rai R, Backos M, Elgaddal S, Shlebak A, Regan L (2002) Factor V Leiden and recurrent miscarriage—prospective outcome of untreated pregnancies. Hum Reprod 17(2):442–445PubMedCrossRefGoogle Scholar
  40. 40.
    Hashimoto K, Shizusawa Shimoya K, Ohashi K, Shimizu T et al (1999) The factor V Leiden mutation in Japanese couples with recurrent abortion. Hum Reprod 14(7):1872–1874PubMedCrossRefGoogle Scholar
  41. 41.
    Martinelli I, Taioli E, Cetin I, Marinoni A, Gerosa S, Villa MV et al (2000) Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 343:1015–1018PubMedCrossRefGoogle Scholar
  42. 42.
    Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748PubMedGoogle Scholar
  43. 43.
    Breslow NE, Day NE (1980) Statistical methods in cancer research. Vol 1. The analysis of case–control studies. IARC Sci Publ 32:335–338Google Scholar
  44. 44.
    Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple graphical test. BMJ 315:629–634PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Balasch J, Reverter JC, Fabregues F, Tassies D, Rafel M, Creus M (1997) Vanrell JA First-trimester repeated abortion is not associated with activated protein C resistance. Hum Reprod 12(5):1094–1097PubMedCrossRefGoogle Scholar
  46. 46.
    Grandone E, Margaglione M, Colaizzo D et al (1997) Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 77:822–824PubMedGoogle Scholar
  47. 47.
    Dizon-Townson DS, Kinney S, Branch DW, Ward K (1997) The factor V Leiden mutation is not a common cause of recurrent miscarriage. J Reprod Immunol 34:217–223PubMedCrossRefGoogle Scholar
  48. 48.
    Pauer HU, Neesen J, Hinney B (1998) Factor V Leiden and its relevance in patients with recurrent abortions. Am J Obstet Gynecol 178:629PubMedGoogle Scholar
  49. 49.
    Younis JS, Brenner B, Ohel G, Tal J, Lanir N, Ben-Ami M (2000) 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 43:31–35PubMedCrossRefGoogle Scholar
  50. 50.
    Foka ZJ, Lambropoulos AF, Saravelos H, Karas GB, Karavida A et al (2000) Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod 15(2):458–462PubMedCrossRefGoogle Scholar
  51. 51.
    Rai R, Shlebak A, Cohen H, Backos M, Holmes Z et al (2001) Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 16(5):961–965PubMedCrossRefGoogle Scholar
  52. 52.
    Reznikoff-Etievant MF, Cayol V, Carbonne B, Robert A, Coulet F (2001) Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage. Br J Obstet Gynaecol 108:1251–1254Google Scholar
  53. 53.
    Sackett D, Haynes BR, Guyatt GH, Tugwell P Deciding whether your treatment has done harm in clinical epidemiology: a basic science for clinical medicine. 2nd edition, Little, Brown and Company, pp 285Google Scholar
  54. 54.
    Seligsohn U, Zivelin A (1997) Thrombophilia as multigenic disorder. Thromb Haemost 78:297–301PubMedGoogle Scholar
  55. 55.
    Clark P, Brennand J, Conkie JA (1998) Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Throm Haemost 79:1166–1170Google Scholar
  56. 56.
    Cumming AM, Tait RC, Fildes S (1995) Development of resistance to activated protein C during pregnancy. Brit J Haematol 90:725–727CrossRefGoogle Scholar
  57. 57.
    Burton GJ, Jauniaux E, Watson AL (1999) Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am J Obstet Gynecol 181:718–724PubMedCrossRefGoogle Scholar
  58. 58.
    Dizon-Townson DS, Meline L, Nelson LM, Varner M, Ward K (1997) Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 177:402–405PubMedCrossRefGoogle Scholar
  59. 59.
    Mousa HA, Alfirevic Z (2000) Do placental lesions reflect thrombophilia state in women with adverse pregnancy outcome? Hum Reprod 15:1830–1833PubMedCrossRefGoogle Scholar
  60. 60.
    Rai R (2000) Obstetric management of antiphospholipid antibody syndrome. J Autoimmun 15:203–207PubMedCrossRefGoogle Scholar
  61. 61.
    Rai R, Cohen H, Dawe M, Regan L (1997) Randomized controlled trial of aspirin plus heparin in pregnant women with recurrent miscarriage associated with antiphospholipid antibodies. BMJ 314:253–257PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Ioannidis JP, Haidich AB, Pappa M et al (2001) Comparison of evidence of treatment effects in randomized and nonrandomized studies. JAMA 286:821–830PubMedCrossRefGoogle Scholar
  63. 63.
    McKee M, Britton A, Black N et al (1999) Methods in health services research. Interpreting the evidence: choosing between randomized and nonrandomized studies. BMJ 319:312–315PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Kunz R, Oxman AD (1998) The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. BMJ 317:1185–1190PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Egger M, Davey Smith G, Schneider M (2001) Systematic reviews of observational studies. In: Egger M, Davey Smith G, Altman D (eds.) BMJ Publishing Group, London pp 211–227Google Scholar
  66. 66.
    Moher D, Fortin P, Jadad AR et al (1996) Completeness of reporting of trials published in languages other than English: implications for conduct and reporting of systematic reviews. Lancet 347:363–366PubMedCrossRefGoogle Scholar
  67. 67.
    Berlin JA, Miles CG, Cirigliano MD, et al. (1997) Does blinding of readers affect the results of meta-analyses? Results of a randomized trial. Online J Current Clin Trials (Doc no 205)Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Division of Anatomical Pathology5B4.09 Walter Mackenzie Health Sciences CentreEdmontonCanada
  2. 2.OMNI Research Group, Department of Obstetrics and GynecologyUniversity of Ottawa Faculty of MedicineOttawaCanada
  3. 3.Ottawa Hospital Research Institute, Box 241OttawaCanada

Personalised recommendations