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
1   Pharmakovigilanzund Beratungszentrum für Embryonaltoxikologie, Berlin, Germany
,
Doreen Hannemann
1   Pharmakovigilanzund Beratungszentrum für Embryonaltoxikologie, Berlin, Germany
,
Reinhard Meister
2   Department of Mathematics, Technische Fachhochschule Berlin, Germany
,
Elisabeth Eléfant
3   Centre Renseignements sur les Agents Teratogènes, Hôpital Armand-Trousseau, Paris, France
,
Wolfgang Paulus
4   Institut für Reproduktionstoxikologie, Ravensburg, Germany
,
Thierry Vial
5   Centre Antipoison – Centre de Pharmacovigilance, Hospices Civils, Lyon, France
,
Minke Reuvers
6   Teratology Information Service, National Institute of Public Health and Environment, Bilthoven, The Netherlands
,
Elisabeth Robert-Gnansia
7   Institut Européen des Génomutations, Lyon, France
,
Judy Arnon
8   Israel Teratogen Information Service, Israel Ministry of Health, Israel
,
Marco De Santis
9   Telefono Rosso – Teratology Information Service, Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy
,
Maurizio Clementi
10   Servizio di Informazione Teratologica, Genetica Clinica ed Epidemiologica, University of Padua, Padua, Italy
,
Elvira Rodriguez-Pinilla
11   Servicio de Informacion Telefonica sobre Teratogenos Español, Centro de Investigación sobre Anomalías Congénitas, Instituto de Salud Carlos III, Madrid, Spain
,
Alla Dolivo
12   Swiss Teratogen Information Service, Lausanne, Switzerland
,
Paul Merlob
13   Beilinson Teratology Information Service, Department of Neonatology, Rabin Medical Centre, Tel Aviv, Israel
› Author Affiliations

Financial support: The Pharmakovigilanzund Beratungszentrum für Embryonaltoxikologie, Berlin is supported by the Pharmakovigilanz Projekt of the Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM). The Institut Européen des Génomutations Lyon is supported by the Fondation Groupama.
Further Information

Publication History

Received 22 February 2006

Accepted after revision 04 May 2006

Publication Date:
30 November 2017 (online)

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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.