Vitamin K antagonists and pregnancy outcome

Christof Schaefer; Doreen Hannemann; Reinhard Meister; Elisabeth Eléfant; Wolfgang Paulus; Thierry Vial; Minke Reuvers; Elisabeth Robert-Gnansia; Judy Arnon; Marco De Santis; Maurizio Clementi; Elvira Rodriguez-Pinilla; Alla Dolivo; Paul Merlob

doi:10.1160/TH06-02-0108

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2006; 95(06): 949-957
DOI: 10.1160/TH06-02-0108

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Vitamin K antagonists and pregnancy outcome

A multi-centre prospective study

Christof Schaefer

¹Pharmakovigilanzund Beratungszentrum für Embryonaltoxikologie, Berlin, Germany

,

Doreen Hannemann

¹Pharmakovigilanzund Beratungszentrum für Embryonaltoxikologie, Berlin, Germany

,

Reinhard Meister

²Department of Mathematics, Technische Fachhochschule Berlin, Germany

,

Elisabeth Eléfant

³Centre Renseignements sur les Agents Teratogènes, Hôpital Armand-Trousseau, Paris, France

,

Wolfgang Paulus

⁴Institut für Reproduktionstoxikologie, Ravensburg, Germany

,

Thierry Vial

⁵Centre Antipoison – Centre de Pharmacovigilance, Hospices Civils, Lyon, France

,

Minke Reuvers

⁶Teratology Information Service, National Institute of Public Health and Environment, Bilthoven, The Netherlands

,

Elisabeth Robert-Gnansia

⁷Institut Européen des Génomutations, Lyon, France

,

Judy Arnon

⁸Israel Teratogen Information Service, Israel Ministry of Health, Israel

,

Marco De Santis

⁹Telefono Rosso – Teratology Information Service, Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy

,

Maurizio Clementi

¹⁰Servizio di Informazione Teratologica, Genetica Clinica ed Epidemiologica, University of Padua, Padua, Italy

,

Elvira Rodriguez-Pinilla

¹¹Servicio de Informacion Telefonica sobre Teratogenos Español, Centro de Investigación sobre Anomalías Congénitas, Instituto de Salud Carlos III, Madrid, Spain

,

Alla Dolivo

¹²Swiss Teratogen Information Service, Lausanne, Switzerland

,

Paul Merlob

¹³Beilinson Teratology Information Service, Department of Neonatology, Rabin Medical Centre, Tel Aviv, Israel

› Author Affiliations

Abstract

Summary

Vitamin K antagonists (VKA) are known to act as teratogens; however, there is still uncertainty about the relative risk for birth defects and the most sensitive period. In a multi-centre (n=12), observational, prospective study we compared 666 pregnant women exposed to phenprocoumon (n=280), acenocoumarol (n=226), fluindione (n=99), warfarin (n=63) and phenindione (n=2) to a non-exposed control group (n=1,094). Data were collected by institutes collaborating in the European Network of Teratology Information Services (ENTIS) during individual risk counselling between 1988 and 2004. Main outcome measures were coumarin embryopathy and other birth defects, miscarriage rate, birth-weight, and prematurity. The rate of major birth defects after 1st trimester exposure was significantly increased (OR 3.86, 95% CI 1.86–8.00). However, there were only two coumarin embryopathies (0.6%; both phenprocoumon). Prematurity was more frequent (16.0% vs. 7.6%, OR 2.61, 95% CI 1.76–3.86), mean gestational age at delivery (37.9 vs. 39.4, p<0.001), and mean birth weight of term infants (3,166 g vs. 3,411 g; p<0.001) were lower compared to the controls. Using the methodology of survival analysis, miscarriage rate reached 42% vs. 14% (hazard ratio 3.36; 95% CI 2.28–4.93). In conclusion, use of VKA during pregnancy increases the risk of structural defects and other adverse pregnancy outcomes.The risk for coumarin embryopathy is, however, very small, in particular when therapy during the 1st trimester did not take place later than week 8 after the 1st day of the last menstrual period. Therefore, elective termination of a wanted pregnancy is not recommended if (inadvertent) exposure took place in early pregnancy. Close follow-up by the obstetrician including level II ultrasound should be recommended in any case of VKA exposure during pregnancy.

Key words

Pregnancy - coumarin derivatives - vitamin K antagonists - human - teratogenicity - spontaneous abortion

Full Text

References

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