Position Statement: Guidelines for vitamin K prophylaxis in newborns: A joint statement of the Canadian Paediatric Society and the College of Family Physicians of Canada.

Newborns are at risk for vitamin K deficiency bleeding (VKDB) caused by inadequate prenatal storage and deficiency of vitamin K in breast milk. Systematic review of evidence to date suggests that a single intramuscular (IM) injection of vitamin K at birth effectively prevents VKDB. Current scientific data suggest that single or repeated doses of oral (PO) vitamin K are less effective than IM vitamin K in preventing VKDB. The Canadian Paediatric Society and the College of Family Physicians of Canada recommend routine IM administration of a single dose of vitamin K at 0.5 mg to 1.0 mg to all newborns. Administering PO vitamin K (2.0 mg at birth, repeated at 2 to 4 and 6 to 8 weeks of age) should be confined to newborns whose parents decline IM vitamin K. Health care providers should clarify with parents that newborns are at increased risk of VKDB if such a regimen is chosen. Current evidence is insufficient to recommend routine intravenous vitamin K administration to preterm infants undergoing intensive care.Keywords HDNB; Newborn; Prophylaxis; Vitamin K; VKDB.

Document de principes : Lignes directrices sur la prophylaxie à la vitamine K chez les nouveau-nés: Une déclaration conjointe de la Société canadienne de pédiatrie et du Collège des médecins de famille du Canada.

Les nouveau-nés sont vulnérables à une hémorragie par carence en vitamine K (HCVK) en raison de réserves prénatales insuffisantes et d'un déficit de vitamine K dans le lait maternel. D'après une analyse systématique des données probantes jusqu'à présent, une injection unique de vitamine K par voie intramusculaire (IM) à la naissance prévient l'HCVK avec efficacité. Selon les données scientifiques actuelles, une dose unique ou des doses répétées de vitamine K par voie orale (PO) sont moins efficaces pour prévenir l'HCVK que la vitamine K IM. La Société canadienne de pédiatrie et le Collège des médecins de famille du Canada recommandent l'administration IM systématique d'une dose unique de 0,5 mg à 1,0 mg de vitamine K à tous les nouveau-nés. L'administration de vitamine K PO (2,0 mg à la naissance, repris à l'âge de deux à quatre semaines et de six à huit semaines) doit être réservée aux nouveau-nés dont les parents refusent l'administration de vitamine K IM. Les dispensateurs de soins devraient expliquer aux parents que leur nouveau-né court un plus grand risque d'HCVK si cette posologie est privilégiée. Les données probantes actuelles sont insuffisantes pour recommander l'administration systématique de vitamine K par voie intraveineuse aux nouveau-nés prématurés en soins intensifs.Mots-clés HDNB; Newborn; Prophylaxis; Vitamin K; VKDB.

Guidelines for vitamin K prophylaxis in newborns.

Newborns are at risk for vitamin K deficiency bleeding (VKDB) caused by inadequate prenatal storage and deficiency of vitamin K in breast milk. Systematic review of evidence to date suggests that a single intramuscular (IM) injection of vitamin K at birth effectively prevents VKDB. Current scientific data suggest that single or repeated doses of oral (PO) vitamin K are less effective than IM vitamin K in preventing VKDB. The Canadian Paediatric Society and the College of Family Physicians of Canada recommend routine IM administration of a single dose vitamin K at 0.5 mg to 1.0 mg to all newborns. Administering PO vitamin K (2.0 mg at birth, repeated at 2 to 4 and 6 to 8 weeks of age), should be confined to newborns whose parents decline IM vitamin K. Health care providers should clarify with parents that newborns are at increased risk of VKDB if such a regimen is chosen. Current evidence is insufficient to recommend routine intravenous vitamin K administration to preterm infants undergoing intensive care.

Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.

Methylmalonic aciduria and homocystinuria, cblC type, is a rare disorder of intracellular vitamin B(12) (cobalamin [Cbl]) metabolism caused by mutations in the MMACHC gene. MMACHC was sequenced from the gDNA of 118 cblC individuals. Eleven novel mutations were identified, as well as 23 mutations that were observed previously. Six sequence variants capture haplotype diversity in individuals across the MMACHC interval. Genotype-phenotype correlations of common mutations were apparent; individuals with c.394C>T tend to present with late-onset disease whereas patients with c.331C>T and c.271dupA tend to present in infancy. Other missense variants were also associated with late- or early-onset disease. Allelic expression analysis was carried out on human cblC fibroblasts compound heterozygous for different combinations of mutations including c.271dupA, c.331C>T, c.394C>T, and c.482G>A. The early-onset c.271dupA mutation was consistently underexpressed when compared to control alleles and the late-onset c.394C>T and c.482G>A mutations. The early-onset c.331C>T mutation was also underexpressed when compared to control alleles and the c.394C>T mutation. Levels of MMACHC mRNA transcript in cell lines homozygous for c.271dupA, c.331C>T, and c.394C>T were assessed using quantitative real-time RT-PCR. Cell lines homozygous for the late onset c.394C>T mutation had significantly higher levels of transcript when compared to cell lines homozygous for the early-onset mutations. Differential or preferential MMACHC transcript levels may provide a clue as to why individuals carrying c.394C>T generally present later in life.

Epigenetic modification of the gene for the vitamin B(12) chaperone MMACHC can result in increased tumorigenicity and methionine dependence.

Methionine dependence, the inability of cells to grow when the amino acid methionine is replaced in culture medium by its metabolic precursor homocysteine, is characteristic of many cancer cell lines and some tumors in situ. Most cell lines proliferate normally under these conditions. The methionine dependent tumorigenic human melanoma cell line MeWo-LC1 was derived from the methionine independent non-tumorigenic line, MeWo. MeWo-LC1 has a cellular phenotype identical to that of cells from patients with the cblC inborn error of cobalamin metabolism, with decreased synthesis of cobalamin coenzymes and decreased activity of the cobalamin-dependent enzymes methionine synthase and methylmalonylCoA mutase. Inability of cblC cells to complement the defect in MeWo-LC1 suggested that it was caused by decreased activity of the MMACHC gene. However, no potentially disease causing mutations were detected in the coding sequence of MMACHC in MeWo-LC1. No MMACHC expression was detected in MeWo-LC1 by quantitative or non-quantitative PCR. There was virtually complete methylation of a CpG island at the 5'-end of the MMACHC gene in MeWo-LC1, consistent with inactivation of the gene by methylation. The CpG island was partially methylated (30-45%) in MeWo and only lightly methylated (2-11%) in control fibroblasts. Infection of MeWo-LC1 with wild type MMACHC resulted in correction of the defect in cobalamin metabolism and restoration of the ability of cells to grow in medium containing homocysteine. We conclude that epigenetic inactivation of the MMACHC gene is responsible for methionine dependence in MeWo-LC1.