Vitamin K prophylaxis revisited : Focus on risk factors

In this thesis the overall efficacy of the Dutch vitamin K prophylaxis regimen in protecting infants against Vitamin K Deficiency Bleeding (VKDB) was investigated by focusing on two major risk factors: cholestatic jaundice and feeding type. We first compared the risk of VKDB under different prophylactic regimens in infants with biliary atresia the largest cause of cholestatic jaundice in infancy . The relative risk of a bleeding in breastfed compared with formula-fed infants was 77.5 for the Dutch prophylaxis (consisting of 25 mcg of daily oral prophylaxis), 7.2 for 1 mg of weekly oral prophylaxis, and 9.3 for 2 mg of intramuscular prophylaxis at birth. The risk of VKDB in infants presenting with cholestasis due to A1ATD on the Dutch prophylaxis was similar (~80 percent), despite marked variations in the degree of cholestasis. It was concluded that the Dutch regimen fails to prevent bleedings in apparently healthy infants with unrecognized cholestasis - irrespective of underlying etiology. Discrepant data from Dutch surveillance studies led us to assess changes in breastfeeding rate and the risk of VKDB over time in infants with BA or A1ATD. While the overall incidence of breastfeeding in Dutch newborns changed only marginally, the breastfeeding rate in infants presenting with BA/A1ATD increased from 6/45 (13%) infants in 1991-1994 to 21/44 (47%) in 2003-2006. This increase was paralleled by a quadrupling of the incidence of VKDB in this cohort from 11 to 41%.Thus, the lack of efficacy of the Dutch regimen, previously masked by the high degree of protection offered by formula feeding, was unveiled by a rising breastfeeding rate in infants with (cholestatic) jaundice. Analysis of formula-fed infants with BA or A1ATD suggests that- in contrast with infants on regular formula - the risk of VKD is substantial in infants fed by hydrolysed formula. The high risk of VKDB in cholestatic infants is thought to be due to the poor absorption of vitamin K in the absence of bile. Due to its hydrophobicity, trafficking of Vitamin K to the enterocytes critically depends on micellar incorporation. Therefore, the efficacy of interventions to improve the absorption of vitamin K in the absence of bile was investigated. First we assessed the ability of polymeric micelles to enable gastrointestinal absorption of vitamin K. To that end, vitamin K was encapsulated in micelles composed of mPEG5000-b-p(HPMAm-lac2), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p