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Background: Due to maldigestion of dietary lipids, fat soluble vitamins are prone to malabsorption in cystic fibrosis (CF) patients with pancreatic insufficiency (PICF). Routine supplementation of vitamin K(1) in PICF is presently subject of discussion., Methods: Serum vitamin K, prothrombin time, PIVKA-II ('liver marker', by two different ELISAs), hydroxyapatite binding capacity (HBC, 'bone marker') and ApoE genotypes were measured in 32 PICF patients (age: 7 months to 25 years) with (PICFK) or without (PICFN) oral vitamin K(1) supplementation, all receiving lipase supplementation, and in 18 healthy controls (C)., Results: PIVKA-II was positive only in 4/7 PICFN. HBC medians of all groups were 57-60%. HBC values of PIVKA-II positive patients were below HBC median of their group. There was no correlation between HBC and PIVKA-II. There was no correlation between prothrombin time and other measurements. HBC medians with regard to ApoE were ApoE2/3 (62.9%)>ApoE3/3 (57.6%)>ApoE3/4+ApoE4/4=(56.65%)., Conclusions: Vitamin K deficiency of liver or bone may occur independently. Prothrombin time is an insensitive marker. Individuals with ApoE4 allels might be more susceptible to osteopenia. As high expenditures are necessary to detect patients at risk, routine vitamin K supplementation for all PICF patients appears appropriate.

Objective: To determine whether the use of mixed micellar vitamin K improves the efficacy of the 3 x 2 mg oral vitamin K prophylaxis schedule., Design: Nationwide active surveillance for vitamin K deficiency bleeding (VKDB) complemented with two surveys on the use of the mixed micellar preparation in hospitals and by paediatricians., Setting and Patients: Infants in Germany in 1997-2000., Intervention: Prophylaxis with three oral doses of 2 mg mixed micellar vitamin K., Main Outcome Measure: Confirmed VKDB between day 8 and week 12 and no condition requiring specific vitamin K supplementation known before the onset of bleeding., Results: Twenty nine reports met the case definition: seven had not received any vitamin K prophylaxis; for three, vitamin K prophylaxis was unknown; two had insufficient vitamin K prophylaxis for their age; 17 had been given the recommended doses. The mixed micellar preparation had been given to seven, other preparations to nine, and one had been given both. These cases did not differ with respect to the site of bleeding and cholestasis detected at bleeding. Estimates of the use of the mixed micellar preparation in birth hospitals and by paediatricians yielded 1 817 769 newborns exposed to the mixed micellar preparation and 1 320 926 newborns exposed to other preparations. The rate of late VKDB was 0.44/100 000 (95% confidence interval (CI) 0.19 to 0.87) in children given mixed micellar vitamin K compared with 0.76/100 000 (95% CI 0.36 to 1.39) in children given other preparations., Conclusion: Mixed micellar vitamin K did not significantly improve the efficacy of the 3 x 2 mg oral vitamin K prophylaxis schedule.

A 1 mg dose of vitamin K given intramuscularly at birth prevents almost all cases of late VKDB, whereas even two oral doses of 1 mg vitamin K given in the first week and a third given in week 5 to 6 are less effective. Is efficacy improved by increasing the dose to 3 x 2 mg? For active surveillance of VKDB, monthly postcards which include a nothing-to-report option, were sent to all heads of pediatric hospitals in Germany from January 1995 to December 1998. All reports were validated according to a standard case definition for late VKDB by means of a questionnaire. The incidence of VKDB with three oral doses of 2 mg vitamin K is compared to previously published rates for VKDB on 3 oral 1 mg oral doses, which had been ascertained with the same surveillance scheme. The number of cases of VKDB (excluding the failure-of-management cases) in children aged 8 days to 12 completed weeks during the 4 year period was 23. 14 had intracranial hemorrhage, 22 had been exclusively breastfed, and in 20 cholestasis was detected after the bleeding episode. 14/23 had been given all recommended 2 mg doses for vitamin K prophylaxis. Until 1996 all had been given the cremophor vitamin K preparation, whereas in 1997 to 1998 two children with late VKBD had received the new mixed micellar (MM) preparation, first licensed in July 1996. The incidence of VKBD per 100,000 live births during the 1995 to 1998 period was 0.72, including children given no vitamin K prophylaxis, and 0.44 for children who had received all age-related recommended vitamin K doses. These incidence rates are significantly lower than those previously published for the 3 x 1 mg dose regimen in Germany (1.8 cases of late VKDB per 100,000 live births in children who had received all recommended vitamin K doses). Not all cases of late VKDB, however, are prevented by the 3 x 2 mg dose regimen, even if the new mixed micellar preparation is given instead of the cremophor preparation.

Oral and intramuscular phytomenadione (vitamin K1) prophylaxis became an issue following the report of a potential carcinogenic effect of intramuscular but not oral phytomenadione prophylaxis. There is increasing evidence, however, that oral phytomenadione prophylaxis is less effective for the prevention of late vitamin K deficiency bleeding (VKDB) than intramuscular prophylaxis. Following a report of an increased cancer risk after intramuscular phytomenadione, a series of papers on this issue appeared. Although an increased risk for solid tumours could almost certainly be excluded, a potential risk for acute lymphatic leukaemia in childhood could not be ruled out definitively. Almost all cases of late VKDB are preventable with intramuscular phytomenadione prophylaxis administered once at birth, whereas a single oral dose given at birth is much less effective. Repeated oral phytomenadione doses given to breast-fed infants either weekly (1 mg) or daily (25 microg) seem to be as effective as intramuscular phytomenadione prophylaxis. The efficacy of 3 oral 2mg doses with the new mixed micellar preparation ('Konakion MM') remains to be established. Although a number of studies have failed to confirm a cancer risk with phytomenadione, these studies have been unable to rule out a risk definitely because absence of evidence is not evidence of absence. A meta-analysis of the available studies might provide 95% confidence intervals narrow enough to exclude even a small cancer risk with some certainty. Oral prophylaxis will probably be as safe as the intramuscular prophylaxis if given daily (25 microg) or weekly (1 mg).

Unlabelled: There is consensus that late vitamin K deficiency bleeding (VKDB) should be prevented by vitamin K prophylaxis. One single dose of 1 mg vitamin K1 is effective if given i.m. or s.c., but not if given orally. Repeated oral doses might be as effective as the parenteral dose but the optimal dose regimen remains to be established. Different oral dose schedules are presently used in different countries. In Australia, Germany, The Netherlands and Switzerland active surveillance data on late VKDB were collected in a similar manner and failure rates compared. Identical case definitions were used. There were three basic strategies for oral and one for parenteral vitamin K prophylaxis for healthy newborns in the four countries: (1) daily supplementation of low dose vitamin K (25 micrograms) for breast-fed infants (The Netherlands); (2) 3 x 1 mg orally [Australia (January 1993-March 1994) and Germany (December 1992-December 1994)]; (3) 1 mg vitamin K i.m. (Australia since March 1994); and (4) 2 x 2 mg vitamin K (new mixed micellar preparation) (Switzerland). The respective failure rates per 100,000 live births (including cases given all recommended doses and those given incomplete prophylaxis) were for strategy: (1) 0.2 (0-1.3) in The Netherlands; (2) 2.3 (95% CI 1.6-3.4) in Germany and 2.5 (1.1-4.8) in Australia (oral prophylaxis); (3) Australia (i.m. prophylaxis) 0 (0-0.9); and (4) 3.6 (0.7-10.6) in Switzerland. The failure rates for complete prophylaxis only were: strategy (1) 0 (0-0.7) in The Netherlands; (2) 1.8 (1.1-2.8) in Germany and 1.5 (0.5-3.6) in Australia; (3) Australia (i.m.) 0 (0-0.9); and (4) 1.2 (0-6.5) in Switzerland., Conclusions: The Australian data confirm that three oral doses of 1 mg vitamin K are less effective than i.m. vitamin K prophylaxis. A daily low oral dose of 25 micrograms vitamin K1 following an initial oral dose of 1 mg after birth for exclusively breast-fed infants may be as effective as parenteral vitamin K prophylaxis. The effectiveness of the "mixed-micellar" preparation of vitamin K1 needs further study.

This article reviews our current knowledge of the assessment of vitamin K status in the human infant, where a deficiency state has been described. Laboratory measures for the functional assessment of vitamin K-dependent coagulation factors as well as the quantitative assay for vitamin K1 (phylloquinone) are reviewed. In addition, four different methods of measuring abnormal prothrombin, a protein induced by vitamin K absence (PIVKA-II), and its use in clinical pediatrics are discussed. Finally, additional methods are briefly described for assessing vitamin K status, including serum osteocalcin, urinary excretion of gamma-carboxyglutamic acid, and deficiencies of the enzymes necessary for the regeneration of phylloquinone in the so-called vitamin K cycle.

The efficacy of vitamin K prophylaxis (1 mg im or sc, or 1-2 mg orally both given as a single dose at birth) in the prevention of vitamin K deficiency bleeding in early infancy was estimated in Germany during a 15-month period between 1988 and 1989. Cases were identified by a survey of all paediatric hospitals and population denominators by a survey of all obstetric hospitals. Response rates were 85% and 68%, respectively. Thirteen cases of vitamin K deficiency bleeding in early infancy with confirmed prophylactic states were confirmed, seven of whom had intracranial haemorrhage. The estimated efficacy of single parenteral administration of vitamin K versus no prophylaxis was 96.7% (95% confidence interval: 74-99.6%) and for single oral administration versus no prophylaxis 80.4% (9.1-95.6%). Single parenteral vitamin K prophylaxis gave substantial protection against vitamin K deficiency bleeding in early infancy. Single oral prophylaxis appeared to be less effective, although the difference was not significant, as indicated by the wide overlap of the respective 95% confidence intervals.

Two breast fed infants had late manifestations of Vitamin K deficiency. No underlying disease was found in the first case. The second patient was found to have alpha 1-Antitrypsin deficiency (Pi type ZZ). The latter patient initially responded well to a single dose of vitamin K administered orally (3 mg). However, three weeks later, he was admitted to our hospital with severe intracranial hemorrhage due to severe vitamin K deficiency. Vitamin K requirements in infants and clinical characteristics of vitamin K deficiency in infants older than 1 week are discussed.

Using a sensitive electrochemical assay for vitamin K1 and standardized techniques for breast-milk collection, we studied the vitamin K1 content of human milk during the first 5 wk of lactation with respect to 1) individual and interindividual differences, 2) the relationship of vitamin K1 to other lipids, and 3) the influence of oral supplements of vitamin K1 on breast milk concentrations. Comparison of fore and hind milk from the mothers revealed higher vitamin K1 concentrations in hindmilks, suggesting that the lipid content influences the vitamin K1 concentration in maternal milk. Samples of maternal milk from nine mothers collected from day 1 to day 36 of lactation showed significantly higher vitamin K1 concentrations in colostral milk than in mature milk. For colostral milk there was a significant correlation of vitamin K1 to cholesterol (r = 0.62) but not to total lipid or phospholipid suggesting a role for cholesterol in the secretion of vitamin K1 into colostral milk. For mature milk correlation coefficients of vitamin K1 with all lipids were low (r = 0.29-0.37) suggesting that at later stages of lactation dietary fluctuations of vitamin K1 may be a more important determinant of the vitamin K1 content of breast milk than the lipid composition. To test the influence of diet, mothers were given oral supplements of vitamin K1.(ABSTRACT TRUNCATED AT 250 WORDS)

Discussion about vitamin K prophylaxis has again become a matter of major concern since cases of life threatening bleeding due to late onset vitamin K deficiency have been observed in Germany. This review tries to summarize present knowledge about the clinical presentation, pathogenesis and the potential prevention of vitamin K deficiency caused bleeding in the neonatal period and infancy.

The incidence of acarboxy-prothrombin and the clotting activity of factors II and VII were evaluated on the fifth day of life in 183 healthy newborns, who had received no vitamin K prophylaxis. Acarboxy-prothrombin was detected in 93/183 newborns. All acarboxy-prothrombin-negative babies had factors II and VII clotting activities above 25% whereas a great variability was observed in acarboxy-prothrombin-positive babies: 21/93 had factor II and 14/93 had factor VII activities below 25%. Seventy-two of the acarboxy-prothrombin-positive babies had normal factor II and VII clotting times on the fifth day of life. These babies must be suspected to have had vitamin K deficiency on one of the first 4 days, as acarboxy-prothrombin has a 50% disappearance rate of 50 h. Acarboxy-prothrombin was mainly observed in breast-fed infants (84/122) and only rarely detectable in infants receiving supplementary (7/44) or exclusive formula feeding (2/17). The type of milk feeding however might be less important for the babies' vitamin K supply than the actual milk intake. All acarboxy-prothrombin-positive babies had received small amounts of milk on the first 4 days of life. In those with low factor II and VII clotting activities the milk intake was low throughout the first 4 days of life, whereas babies with acarboxy-prothrombin and and normal clotting activities had increased their milk intake to more than 100 ml on the third and fourth day of life. Recommendations for vitamin K prophylaxis in newborns should be given with regard to the feeding on the first days of life.

Vitamin K has regained paediatric interest due to a recurrence of bleeding caused by deficiency of the vitamin in newborns and young infants. Increasing awareness of these clinical problems, the development of new methods for the detection of vitamin K deficiency and the direct measurement of vitamin K in tissues have stimulated research. Much new data obtained from these studies has proved helpful to the understanding of vitamin K deficiency in infancy. For example low concentrations of vitamin K have been found in fetal and neonatal livers. The implications of these findings with respect to manifest vitamin K deficiency and to new methods for detection of subclinical vitamin K deficiency are discussed. Breast-feeding is a major risk factor for classical haemorrhagic disease of the newborn and for late onset bleeding due to vitamin K deficiency in young infants. The interdependencies between breast-feeding and vitamin K deficiency are discussed on the basis of new data obtained from direct measurement of vitamin K in maternal milk. The review further focuses on pathophysiological concepts of bleeding due to vitamin K deficiency in infancy and current concepts of vitamin K prophylaxis.