Fetal warfarin syndrome

Abstract

A case of a baby born preterm with an antenatal diagnosis of aortic coarctation for which prostin was electively started at birth. The baby was found to be profoundly anaemic with no clear obstetric cause. Features consistent with antenatal intracerebral haemorrhage were noted on cranial ultrasonography in the context of severe coagulopathy, prompting investigations which confirmed fetal-maternal haemorrhage. It transpired that, following aortic and mitral valve replacements, the mother was anticoagulated with warfarin at conception, having misunderstood her cardiologist's advice that: 'you cannot get pregnant whilst on warfarin'. Following conversion to low molecular weight heparin, she suffered a stroke, thus warfarin was restarted, with an international normalised ratio of 3-4.7 during pregnancy. Following transfer to the paediatric intensive care unit, fetal warfarin syndrome was diagnosed. The coagulopathy and anaemia were corrected and aortic coarctation was excluded. The baby returned to the neonatal intensive care unit for ongoing care and was discharged home in good condition around his due date. At the present time, there is no clinically overt neurological deficit.

Matrix Gla protein deficiency impairs nasal septum growth, causing midface hypoplasia

“…For instance, inactivating mutations in the gene for VKORC1, which generates the reduced form of vitamin K 1 , and GGCX, which uses it as a co-factor, both lead to vitamin K-dependent clotting factor deficiency and midface hypoplasia (33,34). Similarly, babies born to mothers under anticoagulation therapy with warfarin suffer from warfarin embryopathy and also show midface abnormalities (6). Considering that GGCX/VKORC1 mutations or fetal exposure to warfarin both affect ␥ carboxylation of Gla proteins, it is expected that these conditions would lead to inactivation of the skeletal Gla proteins, e.g.…”

“…Both genetic and epigenetic factors regulating the concerted morphogenesis of two craniofacial tissues, bone and cartilage, may affect craniofacial growth and patterning. Although the primary causes are genetic, maternal exposure to toxic substances and nutritional status during pregnancy may also lead to these inborn deformities (2)(3)(4)(5)(6).…”

“…Although the above developmental anomalies are commonly associated with midface hypoplasia, some rare forms of this disease may have a different etiology that is not yet elucidated. For example, children born to mothers treated with warfarin during pregnancy develop warfarin embryopathy, a disease characterized mainly by brain hemorrhages and severe midface hypoplasia (6,9,19). Warfarin is a commonly prescribed anticoagulant that inhibits vitamin K epoxide reductase (VKORC1), which converts the oxidized form of vitamin K 1 to its reduced form.…”

Role of Matrix Gla protein in midface development: Recent advances

“…Similar features are seen in warfarin embryopathy (Fryns, van Fleteren, Mattelaer, & van den Berghe, 1984;Munroe et al, 1999) Warfarin embryopathy -Seen in children born to mothers treated with warfarin, an anticoagulant. Developmental abnormalities are similar to chondrodysplasia punctata and Keutel syndrome (Starling, Sinha, Boyd, & Furck, 2012;Wainwright & Beighton, 2010) (Franco et al, 1995;Munroe et al, 1999;Wainwright & Beighton, 2010). Although it is known that the inactivation of arylsulfatase E (ARSE) leads to chondrodysplasia punctata, the actual substrate and function of this enzyme are still unknown (Weaver et al, 2014).…”

Pregnancy After Cardiac Surgery

“…Oral anticoagulants when used during the first trimester may thus cause a failure in the synthesis of osteocalcin and Gla matrix protein resulting in nasal hypoplasia and stippling seen on X-ray of proximal epiphyseal growth areas (chondroplasia punctata). Exposure during the second and third trimesters may lead to central nervous system and eye abnormalities (optic atrophy, cataract, blindness, microphthalmia, intraventricular hemorrhage, microcephaly, hydrocephalus, seizures and growth/mental retardation) [11]. The greatest susceptible period for developing warfarin embryopathy is between the sixth to ninth weeks of gestation.…”