Coumarin Embryopathy after Intrauterine Exposure to Vitamin K Antagonists within the First 10 Postmenstrual Weeks

Introduction

Vitamin K antagonists (VKAs) are used for anticoagulation in patients with prosthetic heart valves and with thromboembolism caused by coagulopathies such as antiphospholipid syndrome (APS) (Lim W et al. JAMA 2006; 295: 1050 – 1057; Bates SM et al. Chest 2008; 133: 844S–886S). Vitamin K antagonists cross the placenta and are teratogenic. Chemically diverse VKAs such as warfarin, fluindione, or phenprocoumon are all associated with the same teratogenic pattern which thus appears to be related to vitamin K antagonism itself. Maternal VKA treatment throughout pregnancy is associated with coumarin embryopathy (CE) in up to 7 % of newborns. Cartilage, bone and the developing nervous system contain vitamin K-dependent proteins. Eighty percent of neonates with CE show skeletal anomalies (e. g. mid-face hypoplasia, epiphyseal calcifications), 45 % central nervous malformations (e. g. midline structure defects) and 10 % intracranial hemorrhage. Central nervous malformations may occur when VKAs are given in the 1^st trimester. When given in the 2^nd and 3^rd trimester, intracranial hemorrhage and scarring are the reason for central nervous disorders. The mid-face hypoplasia is considered to be due to ectopic calcification in the septal cartilage, causing a reduction in the longitudinal growth of the nasal septum and associated maxillonasal hypoplasia. There is a controversial discussion as to whether discontinuation of VKAs within the first 6 weeks of pregnancy eliminates the risk of CE. In a European multicenter study based on observational data collected by Teratology Information Services, no cases of CE were noted when VKAs had been discontinued before week 8 after the first day of the last menstrual period (LMP) (Schaefer C et al. Thromb Haemost 2006; 95: 949 – 957).