Anticoagulants, thrombocyte aggregation inhibitors, fibrinolytics and volume replacement agents
Janine E. Polifka, Juliane Habermann, in Drugs During Pregnancy and Lactation (Third Edition), 2015
Coumarin embryopathy
VKAs readily cross the placental barrier and can reach the fetus. The teratogenic risk associated with the use of VKA during pregnancy continues to be of importance because maintaining long-term anticoagulation is essential in women with heart valve replacement. Substitution with LMWH in sufficient doses during the first trimester of pregnancy and prior to delivery improves fetal outcome but increases maternal morbidity and mortality (McLintock 2011, 2013, Abildgaard 2009, Vitale 1999). However, recent studies on the use of warfarin during pregnancy have shown that both maternal and fetal outcomes are greatly improved if low-dose warfarin (≤5 mg/d) is used throughout pregnancy and replaced with LMWH close to delivery (McLintock 2013, De Santo 2012, Malik 2012, Geelani 2005).
The embryotoxicity of VKA, particularly that of warfarin, is well-known. Warfarin has been found to produce a characteristic pattern of malformations in the children of women who took this drug during pregnancy. Common features of this pattern of malformations, collectively called coumarin embryopathy or fetal warfarin syndrome, include nasal hypoplasia, stippled epiphyses, and growth retardation (Hall 1980). In a review of 63 case reports of coumarin embryopathy published after 1955, van Driel (2002a) found that anomalies of the skeleton were the most predominant feature, occurring in 51 (81%) of the 63 cases. Midfacial hypoplasia, that included a small upward pointing nose with indentations between the tip of the nose and nares, depressed nasal bridge, defective development of the nasal septum, micrognathia, a prominent forehead, and a flattened appearance of the face, was described in 47 of the cases. Stippling in the epiphyseal regions (chondrodysplasia punctata) was described in 32 (51%) of the 63 cases, mostly along the axial skeleton, at the proximal femora and in the calcanei. Limb hypoplasia, primarily involving the distal digits, may be found in up to one-third of children with coumarin embryopathy (Pauli 1993). Other anomalies reported and summarized by van Driel (2002a) were CNS abnormalities, disturbances of eye and ear development, abnormal heart development, asplenia syndrome, kidney agenesis, cleft lip, jaw and palate and pulmonary hypoplasia. Minor physical anomalies reported were lowset or poorly developed ears, a high-arched palate, hypertelorism, antimongoloid palpebral fissures, and widely spaced nipples. Hepatopathy lasting up to 4 months of age in addition to features typical of coumarin embryopathy were described in a premature infant whose mother had been treated with phenprocoumon up until 24 weeks of pregnancy (Hetzel 2006). It is likely that the liver dysfunction observed in this infant resulted from a toxic effect of phenprocoumon on the fetus similar to that which occasionally occurs with the drug in adults.