Download PDF
CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2019; 79(07): 697-704
DOI: 10.1055/a-0884-3212
GebFra Science
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Coagulation Biomarkers in Women with Recurrent Miscarriage and Polycystic Ovarian Syndrome: Systematic Review and Meta-Analysis

Koagulationsbiomarker bei Frauen mit habitueller Abortneigung und polyzystischem Ovarsyndrom: eine systematische Übersicht und Metaanalyse
Marcelo Borges Cavalcante
1   Department of Obstetrics and Gynecology, Fortaleza University (UNIFOR), Fortaleza-CE, Brazil
,
Manoel Sarno
2   Department of Obstetrics and Gynecology, Federal University of Bahia (UFBA), Salvador-BA, Brazil
,
Candice Torres de Melo Bezerra Cavalcante
3   Pediatric Cardiac Center, Messejana Hospital Dr. Carlos Alberto Studart Gomes, Fortaleza-CE, Brazil
,
Edward Araujo Júnior
4   Department of Obstetrics, Paulista School of Medicine, Federal University of São Paulo (EPM-UNIFESP), São Paulo-SP, Brazil
,
Ricardo Barini
5   Department of Obstetrics and Gynecology, State University of Campinas (UNICAMP), Campinas-SP, Brazil
› Author Affiliations
Further Information

Publication History

received 27 January 2019
revised 22 March 2019

accepted 26 March 2019

Publication Date:
10 July 2019 (online)

Also available at
   Permissions and Reprints

Abstract

Introduction Pregnant women with polycystic ovarian syndrome (PCOS) have high risk of pregnancy loss. Pathophysiological mechanisms appear to be associated with obesity, hormonal factors, or blood clotting disorders. Our aim is to perform a systematic review and meta-analysis on the relationship between coagulation disorders and risk of recurrent miscarriage (RM) in patients with PCOS and to identify coagulation biomarkers for this condition.

Material and Methods PubMed and MEDLINE databases were searched for publications in English language. The search terms used included “RM”, “polycystic ovary syndrome”, “coagulation disorders”, and “thrombophilia”. Odds ratios (ORs) and 95% confidence intervals (CIs) for miscarriage in different RM groups (with and without PCOS).

Results A total of 575 publications including the search terms were identified. Six studies were included for qualitative analysis, and five were included for quantitative analysis (meta-analysis). We found no association between RM and inherited thrombophilias in patients with PCOS: (1) Factor V Leiden (OR, 0.74; 95% CI, 0.38 – 1.45; p = 0.38); (2) C677T methylenetetrahydrofolate reductase polymorphism (MTHFR) (OR, 1.01; 95% CI, 0.64 – 1.59; p = 0.97); and (3) A1297C MTHFR polymorphism (OR, 1.08; 95% CI, 0.62 – 1.89; p = 0.77). Other potential biomarkers were identified, with emphasis on plasminogen activator inhibitor type 1.

Conclusion Data available in the current literature revealed that there was no association between RM and inherited thrombophilias in patients with PCOS. RM patients with PCOS have a high risk of thromboembolic events.

Zusammenfassung

Einleitung Schwangere Frauen mit polyzystischem Ovarsyndrom (PCOS) haben ein hohes Fehlgeburtsrisiko. Es scheint eine Assoziation zwischen den pathophysiologischen Mechanismen einerseits und Adipositas, hormonellen Faktoren und Koagulationsstörungen andererseits zu geben. Ziel dieser Studie war es, eine systematische Übersicht und eine Metaanalyse über die Beziehungen zwischen Gerinnungsstörungen und dem Risiko wiederholter Fehlgeburten (RM) bei Patientinnen mit PCOS durchzuführen und die Koagulationsbiomarker für diesen Zustand zu identifizieren.

Material und Methode Die Datenbanken von PubMed und MEDLINE wurden nach englischsprachigen Publikationen zu diesem Thema durchsucht. Die hierfür verwendeten Suchbegriffe waren „RM“, „polycystic ovary syndrome“ (polyzystisches Ovarsyndrom), „coagulation disorders“ (Koagulationsstörungen) sowie „thrombophilia“ (Thrombophilie). Die Odds Ratios (ORs) und 95%-Konfidenzintervalle (KIs) für Fehlgeburten wurden für die verschiedenen RM-Gruppen (mit und ohne PCOS) berechnet.

Ergebnisse Insgesamt wurden 575 Artikel mit diesen Suchbegriffen identifiziert. Sechs Studien wurden für die qualitative Analyse und 5 für die quantitative Analyse (Metaanalyse) herangezogen. Wir fanden keine Beziehung zwischen RM und einer vererbten Thrombophilie in Patientinnen mit PCOS: (1) Faktor-V-Leiden (OR, 0,74; 95%-KI, 0,38 – 1,45; p = 0,38); (2) C677T-Methylen-Tetrahydrofolat-Reduktase-Polymorphismus (MTHFR) (OR, 1,01; 95%-KI, 0,64 – 1,59; p = 0,97), und (3) A1297C-MTHFR-Polymorphismus (OR, 1,08; 95%-KI, 0,62 – 1,89; p = 0,77). Es wurden andere potenzielle Biomarker ausgemacht mit einem Schwerpunkt auf den Plasminogen-Aktivator-Hemmer Typ 1.

Schlussfolgerung Die aus der aktuellen Literatur entnommenen Daten zeigten, dass es keine Assoziation zwischen RM und einer vererbten Thrombophilie bei Patientinnen mit PCOS gibt. RM-Patientinnen mit PCOS haben ein höheres Risiko für thromboembolische Ereignisse.

Key words

abortion - biomarker - disturbed ovarian function - polymorphism

Schlüsselwörter

Fehlgeburt - Biomarker - gestörte Ovarfunktion - Polymorphismus
 

  • References

  • 1 Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 1935; 29: 181-191
    CrossrefPubMedGoogle Scholar
  • 2 Azziz R, Adashi EY. Stein and Leventhal: 80 years on. Am J Obstet Gynecol 2016; 214: 247.e1-247.e11
    CrossrefPubMedGoogle Scholar
  • 3 Stein IF, Cohen MR. Surgical treatment of bilateral polycystic ovaries–Amenorrhea and sterility. Am J Obstet Gynecol 1939; 38: 465-480
    CrossrefPubMedGoogle Scholar
  • 4 Bozdag G, Mumusoglu S, Zengin D. et al. The prevalence and phenotypic features of polycystic ovary syndrome: A systematic review and meta-Analysis. Hum Reprod 2016; 31: 2841-2855
    CrossrefPubMedGoogle Scholar
  • 5 Azziz R. Epidemiology and genetics of the polycystic ovary syndrome in adults – UpToDate. Online: https://www.uptodate.com/contents/epidemiology-and-genetics-of-the-polycystic-ovary-syndrome-in-adults last access: 06.11.2018
    PubMedGoogle Scholar
  • 6 Teede HJ, Misso ML, Costello MF. et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110: 364-379
    CrossrefPubMedGoogle Scholar
  • 7 Cooney LG, Dokras A. Beyond fertility: polycystic ovary syndrome and long-term health. Fertil Steril 2018; 110: 794-809
    CrossrefPubMedGoogle Scholar
  • 8 Anagnostis P, Tarlatzis BC, Kauffman RP. Polycystic ovarian syndrome (PCOS): Long-term metabolic consequences. Metabolism 2018; 86: 33-43
    CrossrefPubMedGoogle Scholar
  • 9 Zegers-Hochschild F, Adamson GD, Dyer S. et al. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril 2017; 108: 393-406
    CrossrefPubMedGoogle Scholar
  • 10 Rasmark Roepke E, Matthiesen L, Rylance R. et al. Is the incidence of recurrent pregnancy loss increasing? A retrospective register-based study in Sweden. Acta Obstet Gynecol Scand 2017; 96: 1365-1372
    CrossrefPubMedGoogle Scholar
  • 11 El Hachem H, Crepaux V, May-Panloup P. et al. Recurrent pregnancy loss: current perspectives. Int J Womens Health 2017; 9: 331-345
    CrossrefPubMedGoogle Scholar
  • 12 Chakraborty P, Goswami SK, Rajani S. et al. Recurrent Pregnancy Loss in Polycystic Ovary Syndrome: Role of Hyperhomocysteinemia and Insulin Resistance. PLoS One 2013; 8: e64446
    CrossrefPubMedGoogle Scholar
  • 13 Matjila MJ, Hoffman A, van der Spuy ZM. Medical conditions associated with recurrent miscarriage–Is BMI the tip of the iceberg?. Eur J Obstet Gynecol Reprod Biol 2017; 214: 91-96
    CrossrefPubMedGoogle Scholar
  • 14 Tziomalos K, Dinas K. Obesity and Outcome of Assisted Reproduction in Patients With Polycystic Ovary Syndrome. Front Endocrinol (Lausanne) 2018; 9: 149
    CrossrefPubMedGoogle Scholar
  • 15 Targher G, Zoppini G, Bonora E. et al. Hemostatic and fibrinolytic abnormalities in polycystic ovary syndrome. Semin Thromb Hemost 2014; 40: 600-618
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Manneras-Holm L, Baghaei F, Holm G. et al. Coagulation and fibrinolytic disturbances in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2011; 96: 1068-1076
    CrossrefPubMedGoogle Scholar
  • 17 Burchall GF, Piva TJ, Linden MD. et al. Comprehensive Assessment of the Hemostatic System in Polycystic Ovarian Syndrome. Semin Thromb Hemost 2015; 42: 55-62
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Wolski H, Barlik M, Drews K. et al. Contribution of inherited thrombophilia to recurrent miscarriage in the Polish population. Ginekol Pol 2017; 88: 385-392
    CrossrefPubMedGoogle Scholar
  • 19 Karadağ C, Yoldemir T, Karadağ SD. et al. Obstetric outcomes of recurrent pregnancy loss patients diagnosed wıth inherited thrombophilia. Ir J Med Sci 2017; 186: 707-713
    CrossrefPubMedGoogle Scholar
  • 20 Schreiber K, Sciascia S, de Groot PG. et al. Antiphospholipid syndrome. Nat Rev Dis Prim 2018; 4: 17103
    PubMedGoogle Scholar
  • 21 Arachchillage D, Makris M. Inherited Thrombophilia and Pregnancy Complications: Should We Test?. Semin Thromb Hemost 2018; DOI: 10.1055/s-0038-1657782.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Moher D, Liberati A, Tetzlaff J. et al. PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009; 339: b2535
    CrossrefPubMedGoogle Scholar
  • 23 Glueck CJ, Wang P, Bornovali S. et al. Polycystic ovary syndrome, the G1691A Factor V Leiden mutation, and plasminogen activator inhibitor activity: Associations with recurrent pregnancy loss. Metabolism 2003; 52: 1627-1632
    CrossrefPubMedGoogle Scholar
  • 24 Idali F, Zareii S, Mohammad-Zadeh A. et al. Plasminogen Activator Inhibitor 1 and Methylenetetrahydrofolate Reductase Gene mutations in Iranian Women with Polycystic Ovary Syndrome. Am J Reprod Immunol 2012; 68: 400-407
    CrossrefPubMedGoogle Scholar
  • 25 Moini A, Tadayon S, Tehranian A. et al. Association of thrombophilia and polycystic ovarian syndrome in women with history of recurrent pregnancy loss. Gynecol Endocrinol 2012; 28: 590-593
    CrossrefPubMedGoogle Scholar
  • 26 Kazerooni T, Ghaffarpasand F, Asadi N. et al. Correlation between thrombophilia and recurrent pregnancy loss in patients with polycystic ovary syndrome: A comparative study. J Chinese Med Assoc 2013; 76: 282-288
    PubMedGoogle Scholar
  • 27 Rogenhofer N, Engels L, Bogdanova N. et al. Independent association of the M2/ANXA5 haplotype with recurrent pregnancy loss (RPL) in PCOS patients. Metabolism 2013; 62: 1057-1060
    CrossrefPubMedGoogle Scholar
  • 28 Szafarowska M, Segiet A, Jerzak MM. Methylenotetrahydrololate reductase A1298C and C677T polymorphisms and adverse pregnancy outcome in women with PCOS. Neuro Endocrinl Lett 2016; 37: 141-146
    PubMedGoogle Scholar
  • 29 Shan Y, Wang A, Sun Y. et al. Coagulation and fibrinolytic indices during the first trimester of pregnancy in women with polycystic ovary syndrome: A preliminary study. Reprod Sci 2013; 20: 1390-1397
    CrossrefPubMedGoogle Scholar
  • 30 Li X, Liu Y, Zhang R. et al. Meta-analysis of the association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss. Med Sci Monit 2015; 21: 1051-1056
    CrossrefPubMedGoogle Scholar
  • 31 Turki RF, Assidi M, Banni HA. et al. Associations of recurrent miscarriages with chromosomal abnormalities, thrombophilia allelic polymorphisms and/or consanguinity in Saudi Arabia. BMC Med Genet 2016; 17 (S1): 69
    PubMedGoogle Scholar
  • 32 Barlik M, Seremak-Mrozikiewicz A, Drews K. et al. Correlation between factor VII and PAI-1 genetic variants and recurrent miscarriage. Ginekol Pol 2016; 87: 504-509
    CrossrefPubMedGoogle Scholar
  • 33 Davenport WB, Kutteh WH. Inherited Thrombophilias and Adverse Pregnancy Outcomes. Obstet Gynecol Clin North Am 2014; 41: 133-144
    CrossrefPubMedGoogle Scholar
  • 34 Toth B, Würfel W, Bohlmann M. et al. Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG (S1-Level, AWMF Registry No. 015/050, December 2013). Geburtsh Frauenheilk 2015; 75: 1117-1129
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Kaiser J, Branch DW. Recurrent Pregnancy Loss. Clin Obstet Gynecol 2016; 59: 464-473
    CrossrefPubMedGoogle Scholar
  • 36 Huchon C, Deffieux X, Beucher G. et al. Pregnancy loss: French clinical practice guidelines. Eur J Obstet Gynecol Reprod Biol 2016; 201: 18-26
    CrossrefPubMedGoogle Scholar
  • 37 de Jong PG, Goddijn M, Middeldorp S. Antithrombotic therapy for pregnancy loss. Hum Reprod Update 2013; 19: 656-673
    CrossrefPubMedGoogle Scholar
  • 38 Ye Y, Vattai A, Zhang X. et al. Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases. Int J Mol Sci 2017; 18: 1651
    CrossrefPubMedGoogle Scholar
  • 39 Gris JC, Neveu S, Mares P. et al. Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. J Lab Clin Med 1993; 122: 606-615
    PubMedGoogle Scholar
  • 40 Koiou E, Tziomalos K, Dinas K. et al. Plasma plasminogen activator inhibitor-1 levels in the different phenotypes of the polycystic ovary syndrome. Endocr J 2012; 59: 21-29
    CrossrefPubMedGoogle Scholar
  • 41 Ye Y, Vattai A, Zhang X. et al. Role of Plasminogen Activator Inhibitor Type 1 in Pathologies of Female Reproductive Diseases. Int J Mol Sci 2017; 18: 1651
    CrossrefPubMedGoogle Scholar
  • 42 Burchall G, Piva T, Ranasinha S. et al. Differential Effects on Haemostatic Markers by Metformin and the Contraceptive Pill: A Randomized Comparative Trial in PCOS. Thromb Haemost 2017; 117: 2053-2062
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Kahal H, Aburima A, Ungvari T. et al. The effects of treatment with liraglutide on atherothrombotic risk in obese young women with polycystic ovary syndrome and controls. BMC Endocr Disord 2015; 15: 14
    CrossrefPubMedGoogle Scholar
  • 44 Tzotzas T, Karras S, Katsiki N. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome. Curr Vasc Pharmacol 2017; 15: 218-229
    CrossrefPubMedGoogle Scholar
  • 45 Salamun V, Jensterle M, Janez A. et al. Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. Eur J Endocrinol 2018; 179: 1-11
    CrossrefPubMedGoogle Scholar
  • 46 Skubleny D, Switzer NJ, Gill RS. et al. The Impact of Bariatric Surgery on Polycystic Ovary Syndrome: a Systematic Review and Meta-analysis. Obes Surg 2016; 26: 169-176
    CrossrefPubMedGoogle Scholar
  • 47 Escobar-Morreale HF. Surgical management of metabolic dysfunction in PCOS. Steroids 2012; 77: 312-316
    CrossrefPubMedGoogle Scholar