PDF herunterladen
Thromb Haemost 2017; 117(05): 870-879
DOI: 10.1160/TH16-11-0838
Coagulation and Fibrinolysis
Schattauer GmbH

Pregnancy outcome of first trimester exposure to the vitamin K antagonist phenprocoumon depends on duration of treatment

Eleanor Hüttel
1   Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité - Universitätsmedizin Berlin, Germany
,
Stephanie Padberg
1   Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité - Universitätsmedizin Berlin, Germany
,
Reinhard Meister
2   Department of Mathematics, Beuth Hochschule für Technik Berlin (University of Applied Sciences), Berlin, Germany
,
Evelin Beck   *
1   Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité - Universitätsmedizin Berlin, Germany
,
Christof Schaefer   *
1   Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Charité - Universitätsmedizin Berlin, Germany
› Institutsangaben Financial support: This work was supported by the German Federal Institute for Drugs and Medical Devices (BfArM). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Weitere Informationen

Publikationsverlauf

Received: 07. November 2016

Accepted after major revision: 02. Februar 2017

Publikationsdatum:
28. November 2017 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Summary

The aim of this observational cohort study was to specify the risk of the vitamin K antagonist (VKA) phenprocoumon during first trimester of pregnancy, in particular to estimate the risk of birth defects and spontaneous fetal loss. Four hundred eight pregnancies with phenprocoumon exposure were compared to 1,642 pregnancies neither exposed to VKA nor to other major teratogens or fetotoxicants. There was no typical warfarin embryopathy in our exposed cohort. However, the overall rate of major birth defects was significantly increased (7.4 % vs 2.3 %; adjusted odds ratio [ORadj] 2.14; 95 % confidence interval [CI] 1.4–3.4). With early cessation until five completed gestational weeks the birth defect risk was similar to the comparison cohort (2.4 % vs 2.3 %; ORadj 1.07; 95 % CI 0.2–3.6). With treatment duration exceeding seven gestational weeks the rate of major birth defects increased up to five-fold (10.8 % vs 2.3 %; ORadj 5.18; 95 % CI 2.0–11.6). The overall risk of spontaneous abortion (SAB) was 38.0 % vs 17.5 % in the comparison cohort (adjusted hazard ratio [HRadj] 2.9; 95 % CI 2.2–3.9). The treatment duration had a significant effect on the hazard of SAB (HRadj 1.12; 95 % CI 1.01–1.25 per each additional exposure week). Phenprocoumon and other VKA carry an embryotoxic risk. This risk seems to be time-dependent with a steep risk increase for birth defects and also for fetal loss after week 5. If maternal disease permits, VKA therapy should be switched to safer alternatives such as heparins immediately after early recognition of pregnancy.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Time-dependence - spontaneous abortion - congenital malformation - thrombosis prophylaxis - observational cohort study

* Both authors contributed equally to this article.


 

  • References

  • 1 Hall JG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 1980; 68: 122-140.
    CrossrefPubMedSuche in Google Scholar
  • 2 Howe AM, Webster WS. The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances. Teratology 1992; 46: 379-390.
    CrossrefPubMedSuche in Google Scholar
  • 3 van Driel D, Wesseling J, Sauer PJ. et al. Teratogen update: fetal effects after in utero exposure to coumarins overview of cases, follow-up findings, and pathogenesis. Teratology 2002; 66: 127-140.
    CrossrefPubMedSuche in Google Scholar
  • 4 Becker MH, Genieser NB, Finegold M. et al. Chondrodysplasis punctata: is maternal warfarin therapy a factor?. Am J Dis Child 1975; 129: 356-359.
    CrossrefPubMedSuche in Google Scholar
  • 5 Whitfield MF. Chondrodysplasia punctata after warfarin in early pregnancy. Case report and summary of the literature. Arch Dis Childh 1980; 55: 139-142.
    CrossrefPubMedSuche in Google Scholar
  • 6 Ville Y, Jenkins E, Shearer MJ. et al. Fetal intraventricular haemorrhage and maternal warfarin. Lancet 1993; 341: 1211.
    PubMedSuche in Google Scholar
  • 7 Pauli RM, Lian JB, Mosher DF, Suttie JW. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am J Hum Genet 1987; 41: 566-583.
    PubMedSuche in Google Scholar
  • 8 Schaefer C, Hannemann D, Meister R. et al. Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study. Thromb Haemost 2006; 95: 949-957.
    Thieme ConnectPubMedSuche in Google Scholar
  • 9 Schaefer C, Ornoy A, Clementi M. et al. Using observational cohort data for studying drug effects on pregnancy outcome--methodological considerations. Repr Toxicol 2008; 26: 36-41.
    PubMedSuche in Google Scholar
  • 10 von Elm E, Altman DG, Egger M. et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Intern J Surg 2014; 12: 1495-1499.
    PubMedSuche in Google Scholar
  • 11 EUROCAT (2013). EUROCAT guide 1.4 and reference documents: coding and classification. EUROCAT Central Registry, Ispra, Italy. http://www.eurocat-network.eu/content/Full%20Guide%201?%204.pdf
    PubMed
  • 12 Voigt M, Rochow N, Hesse V. et al. Short communication about percentile values of body measures of newborn babies. Z Geburtshilfe Neonatol 2010; 214: 24-29.
    Thieme ConnectPubMedSuche in Google Scholar
  • 13 D’Agostino Jr. RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998; 17: 2265-2281.
    CrossrefPubMedSuche in Google Scholar
  • 14 McCaffrey DF, Ridgeway G, Morral AR. Propensity score estimation with boosted regression for evaluating causal effects in observational studies. Psychol Meth 2004; 09: 403-425.
    CrossrefPubMedSuche in Google Scholar
  • 15 Meister R, Schaefer C. Statistical methods for estimating the probability of spontaneous abortion in observational studies--analyzing pregnancies exposed to coumarin derivatives. Repr Toxicol 2008; 26: 31-35.
    PubMedSuche in Google Scholar
  • 16 Mitra R, Reiter JP. A comparison of two methods of estimating propensity scores after multiple imputation. Stat Method Med Res 2016; 25: 188-204.
    CrossrefPubMedSuche in Google Scholar
  • 17 Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley; 2004
    Suche in Google Scholar
  • 18 Little RJA, Rubin DB. Statistical Analysis With Missing Data. Wiley; 1987
    Suche in Google Scholar
  • 19 Balde MD, Breitbach GP, Wettstein A. et al. Tetralogy of Fallot following coumarin administration in early pregnancy--an embryopathy?. Geburtshilfe Frauenheilkunde 1988; 48: 182-183.
    PubMedSuche in Google Scholar
  • 20 Hall BD. Warfarin embryopathy and urinary tract anomalies: possible new association. Am J Med Genet 1989; 34: 292-293.
    CrossrefPubMedSuche in Google Scholar
  • 21 Oberlander TF, Warburton W, Misri S. et al. Major congenital malformations following prenatal exposure to serotonin reuptake inhibitors and benzodiazepines using population-based health data. Birth Defects Res Part B Develop Repr Toxicol 2008; 83: 68-76.
    PubMedSuche in Google Scholar
  • 22 Habermann F, Fritzsche J, Fuhlbruck F. et al. Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort study. J Clin Psychopharmacol 2013; 33: 453-462.
    CrossrefPubMedSuche in Google Scholar
  • 23 Scialli AR. Paroxetine exposure during pregnancy and cardiac malformations. Birth Defects Res Part A Clin Mol Teratol 2010; 88: 175-177.
    PubMedSuche in Google Scholar
  • 24 Blickstein D, Blickstein I. The risk of fetal loss associated with Warfarin anticoagulation. Intern J Gynaecol Obst 2002; 78: 221-225.
    PubMedSuche in Google Scholar
  • 25 Sterne JAC, White IR, Carlin JB. et al. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. Br Med J 2009; 338: b2393.
    CrossrefPubMedSuche in Google Scholar
  • 26 Guyatt GH, Akl EA, Crowther M. et al. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (02) Suppl 7s-47s.
    CrossrefPubMedSuche in Google Scholar