title: Effects of oral and intramuscular vitamin K prophylaxis on PIVKA-II assay parameters in breastfed infants in Turkey. EFFECT OF VITAMIN K ADMINISTRATION ON ACARBOXY PROTHROMBIN (PIVKA-II) LEVELS IN NEWBORNS Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K A new mixed micellar preparation for oral vitamin K prophylaxis: randomised controlled comparison with an intramuscular formulation in breast fed infants Vitamin K to Neonates: Peroral versus Intramuscular Administration Vitamin K1 concentration in breast-fed neonates after oral or intramuscular administration of a single dose of a new mixed-micellar preparation of phylloquinone. Effect of oral water soluble vitamin K on PIVKA-II levels in newborns. Effects of oral and intramuscular vitamin K prophylaxis on vitamin K1, PIVKA-II, and clotting factors in breast fed infants. [Effects of the administration of vitamin K on the activity of Factor II, VII and X in healthy newborns]. Comparative study of oral versus injectable vitamin K in neonates. Prevention of subclinical vitamin K deficiency based on PIVKA-II levels: oral versus intramuscular route.
abstract: Protein induced by vitamin K absence ( PIVKA-II ) has been used for the evaluation of vitamin K deficiency in the newborn . Differing PIVKA-II detection rates in various studies on hemorrhagic disease of the newborn have not been explained satisfactorily . In this study we investigated the PIVKA-II values of 44 healthy breastfed infants , of whom 29 received vitamin K1 either orally ( N = 13 ) or intramuscularly ( n = 16 ) , and the remaining 15 constituted the  control group .  PIVKA-II was detected in 15.3 percent ( 2/13 ) of the oral and 25 percent of the ( 4/16 ) intramuscular group on the third day of life . The detection rate was 93.3 percent ( 14/15 ) in the control group . However , at the one-month follow-up , there were no PIVKA-II positive infants . In conclusion , PIVKA-II positivity among breastfed Turkish infants on the third day of life was high compared to that in other studies , perhaps due to a delay in enzyme maturation related to racial , environmental and nutritional factors PIVKA-II ( protein induced by vitamin K absence or antagonist-II ) was measured in two groups of newborns , one group being given 5 mg vitamin K at birth and the other untreated . The untreated group had a significantly higher proportion of PIVKA-II positive babies at 3 and 5 days of age than did the treated group . When vitamin K was administered to newborn babies whose normotest levels were less than 30 % , it was found that the higher the pre-treatment PIVKA-II levels the greater the response to vitamin K , as monitored by the normotest . Thus PIVKA-II levels might be more useful than a coagulation test , since the low activity of vitamin K dependent coagulation factors sometimes reflects not vitamin K deficiency but impaired production of these factors because of immaturity . The findings support the view that vitamin K given prophylactically at birth will help to prevent neonatal bleeding Abstract 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 Netherl and s and Switzerl and 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 μg ) for breast-fed infants ( The Netherl and s ) ; ( 2 ) 3 × 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 × 2 mg vitamin K ( new mixed micellar preparation ) ( Switzerl and ) . 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 Netherl and s ; ( 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 Switzerl and . The failure rates for complete prophylaxis only were : strategy ( 1 ) 0 ( 0–0.7 ) in The Netherl and s ; ( 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 Switzerl and . 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 μg 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 OBJECTIVE To compare a new oral preparation of vitamin K1 ( Konakion MM ) containing lecithin and glycocholic acid with a st and ard intramuscular ( IM ) preparation during the first 8 weeks of life in exclusively breast fed infants . METHODS Infants were r and omised at birth to the IM group ( 1 mg vitamin K )  or the oral group  ( 2 mg given at birth and repeated at 7 and 30 days of life ) . Prothrombin time ( INR ) , plasma vitamin K1 , and PIVKA II ( undercarboxylated prothrombin ) were monitored at 14 , 30 , and 56 days of age . RESULTS Seventy nine infants were r and omised to the oral group and 77 to the IM group . Sixty seven infants in each group completed eight weeks of the study . Prothrombin times did not differ between the two groups . Mean ( SD ) plasma vitamin K1values ( in ng/ml ) decreased in both groups over time , but were higher in the oral group at 14 and 56 days : 2.0 ( 1.6 ) v 1.3 ( 1.1 ) at 14 days ; 0.5 ( 0.3 ) v 0.5 ( 0.7 ) at 30 days ; and 0.5 ( 0.8 ) v 0.2 ( 0.2 ) at 56 days of life . PIVKA II was raised ( ⩾ 0.1 AU/ml ) in cord blood in 47 % of the infants . By 14 days , only one infant in each group had a raised PIVKA II value and both of these initially had high concentrations of PIVKA II in cord blood . At 30 days , there were no raised PIVKA II values . At 56 days , there were no raised PIVKA II values in the oral group , although three infants in the IM group had raised values . CONCLUSIONS Plasma vitamin K concentrations were at least equal or significantly higher in babies given oral vitamin K supplements compared with IM treated babies at the time points measured . Through the first 8 weeks of life , multiple doses of the new oral preparation maintain haemostasis and vitamin K status in breast fed infants at least equal to that of the intramuscular preparation ABSTRACT . In a r and omized study of 300 infants , the effect of 1 mg of peroral vitamin K given at birth was compared to the same dose given as an intramuscular injection . The combined activity of coagulation factor II + VII + X taken after 48 and before 72 hours after delivery served as the primary endpoint . Prothrombin ( antigen ) and PIVKA II ( acarboxyprothrombin ) were also measured . All infants were observed for events of bleeding until discharge from the hospital , normally on the fifth day . No significant differences between the groups in any of the biochemical markers were observed . The 95 % confidence limits of the differences were very narrow for all factors . No cases of bleeding were observed . We conclude that administration of 1 mg peroral vitamin K is as efficient as intramuscular administration of the same dose in the prevention of classical hemorrhagic disease of the newborn The plasma disposition of a new mixed-micellar preparation ( KONAKION MM , Roche ) of phylloquinone ( vitamin K1 ) has been studied in 25 healthy , fully breast-fed , newborn babies , r and omized to receive a single dose of either 1.5 mg i.m . ( 11 babies ) or 3 mg p.o . ( 14 babies ) . Venous blood sample s were collected at 25 h , 4 days , and 24 days . After p.o . administration , the median plasma phylloquinone concentration increased to 89 ng/ml after 24 h , then decreased to 51 ng/ml after 4 days ; the respective concentrations after i.m . injection were 146 ng/ml and 34 ng/ml . The higher plasma phylloquinone level in the i.m . group after 24 h was not statistically significant compared with that of the p.o . group , but the reversed higher concentration in the p.o . group after 4 days was significant ( p < 0.01 ) . After 24 days the median plasma phylloquinone had decreased to 0.44 ng/ml ( range 0.19 - 1.44 ) and 1.05 ng/ml ( range 0.37 - 1.87 ) in the p.o . and i.m . groups , respectively . There was a significant difference between these plasma concentrations ( p < 0.01 ) . They were within or above the reference adult fasting range ( 0.17 - 0.68 ng/ml ) . The narrow range of plasma concentrations at 24 h and 4 days suggests a greater consistency of absorption from this micellar preparation than from other emulsion-based preparations . Further studies are required to assess the long-term protection of a single oral dose against late hemorrhagic disease of the newborn . Until such time , breast-fed babies given this preparation orally should receive ( an ) additional dose(s ) Intramuscular administration of vitamin K for prophylaxis against hemorrhagic disease of the newborn has the disadvantage of increased cost , pain , anxiety to parents and risk of transmission of infection . Oral route is a better alternative . Oral absorption of vitamin K has been shown to be equally good using special oral preparations . However , this preparation is not available in India . A prospect i ve study was carried out on 51 full term , healthy breastfed newborns to evaluate if the injectable water soluble preparation of vitamin K ( menadione sodium bisulphite ) could be as effective . Fourteen babies received 1 mg vitamin K intramuscularly , 24 received 2 mg vitamin K orally while 13 controls did not receive vitamin K at birth .  PIVKA-II levels were measured in cord blood and at 72 - 78 hours of age in all babies as a marker of vitamin K deficiency . The overall PIVKA-II prevalence in cord blood was 64.7 % . At 72 - 78 hours , PIVKA-II was present in 50 % of babies in IM group , 58.3 % of babies in oral group and in 76.9 % of babies in ' no vitamin K ' group ( p > 0.05 ) . The PIVKA-II levels decreased or did not change at 72 - 78 hours in 91.6 % of babies in oral group versus 92.8 % of babies in IM group ( p > 0.05 ) . On the other h and , PIVKA-II levels increased in 30.7 % of babies who did not receive vitamin K as against in 7.8 % of babies receiving vitamin K in either form ( p < 0.05 ) . Hence , vitamin K prophylaxis is required for all newborns at birth and injectable vitamin K ( menadione sodium bisulphite ) given orally to term healthy babies is effective in preventing vitamin K deficiency state A r and omised clinical trial was conducted to establish the effects of oral and intramuscular administration of vitamin K at birth on plasma concentrations of vitamin K1 , proteins induced by vitamin K absence ( PIVKA-II ) , and clotting factors . Two groups of about 165 healthy breast fed infants who received at r and om 1 mg vitamin K1 orally or intramuscularly after birth were studied at 2 weeks and 1 and 3 months of age . Although  vitamin K1 concentrations were statistically significantly higher in the intramuscular group , blood coagulability , activities of factors VII and X and PIVKA-II concentrations did not reveal any difference between the two groups . At 2 weeks of age  vitamin K1 concentrations were raised compared with reported unsupplemented concentrations and no PIVKA-II was detectable . At 3 months  vitamin K1 concentrations were back at unsupplemented values and PIVKA-II was detectable in 11.5 % of infants . Therefore , a repeated oral prophylaxis will be necessary to completely prevent ( biochemical ) vitamin K deficiency beyond the age of 1 month The study was design ed to know the effect of oral vitamin K ( VK ) treatment , on clotting factors II-VII-IX-X and the protein induced by VK absence from factor II ( PIVCA II ) on full term infants . Seventy healthy newborns were studied and each was r and omly placed in one of two groups : Group A , newborns that received  human milk and milk formula ( mixed feeding ) and group B , newborns that were exclusively breast fed . These groups were also divided in two subgroups : I received 2 mg of VK1 orally and II ( control ) did not receive VK .  Clotting activity of the coagulation factors and PIVCA II was determined from blood plasma obtained immediately after birth and 48 hours after VK administration . Basal activity of the factors analyzed was similar in all groups with values ranging from 25 % to 40 % . After 48 hours a significant increase in all factors studied and a decrease of PIVKA II was observed in those children who received oral VK . The results suggest that oral VK effectively increases VK dependent factors and prevents the risk of hemorrhagic disease in the newborn , with the advantage of being less traumatic and less risky to the infant than intramuscular VK One hundred term exclusively breast fed babies weighing more than 2.5 kg were evaluated to determine the efficacy of various modes and doses of Vitamin K to prevent hemorrhagic disease of newborn ( HDN ) . The babies were grouped into four categories of 25 each : Group A--1 mg Vitamin K intramuscular ( Menadione sodium disulphite ) at birth ; Group B--0.5 mg Vitamin K intramuscular ; Group C--1 mg Vitamin K orally , and group D -- no Vitamin K. The prothrombin index was estimated in all babies between 36 - 72 hours of age . The results revealed a prothrombin index in Groups A , B , C and D as 94.98 + /- 7.64 % , 95.08 + /- 9.91 % , 92.51 + /- 10.10 % and 80.39 + /- 15.90 % , respectively . The differences between Groups A , B and C were insignificant . However , Group D , prothrombin index was significantly reduced as compared with the other three groups . It is , therefore , concluded that oral Vitamin K is as effective as injectable Vitamin K and its usage is recommended in our country to reduce complications and costs of parenteral therapy Classical  hemorrhagic disease of newborn ( HDNB )  was first described in 1894(1 ) . Clinical ly manifest classical HDNB is relatively uncommon with incidence of 1 - 2/1000 live births . Exclusively breastfed babies are predisposed to develop HDNB because of absence of bacterial flora in the gut , lack of stores of vitamin K and low vitamin K levels in breastmilk(2,3 ) . In the absence of vitamin K , its precursor non-carboxylated proteins called Proteins Induced in Vitamin K Absence ( PIVKA ) are elevated . Levels of PIVKA-II ( Precursor Protein of Factor II ) are more specific than Pro-thrombin Time ( PT ) because the former does not get elevated in states of decreased synthesis of coagulation factors as occurs in hepatitis(4 ) . The American Academy of Pediatrics ( AAP ) recommends prophylactic administration of intramuscular ( IM ) vitamin K for all newborn babies at birth(5 ) whereas in India , there is lack of consensus and ( IM ) vitamin K is given only to high risk babies in many centers . Intramuscular vitamin K is associated with the potential risks of transmission of viral infections , lymphoreticular malignancies in later childhood and excessive cost . Oral administration of vitamin K is thus preferable because of safety and cost effectiveness . The present study was conducted to look for sub- clinical evidence of  vitamin K deficiency in exclusively breastfed term neonates and evaluate the efficacy of orally and intramuscularly administered water soluble vitamin K in them
target: One dose of vitamin K reduced clinical bleeding at 1 - 7 days , including bleeding after circumcision , and improved biochemical indices of coagulation status .
  There was no evidence of a difference between the oral and intramuscular route in effects on biochemical indices of coagulation status .
  REVIEW ER 'S CONCLUSIONS A single dose ( 1.0 mg ) of intramuscular vitamin K after birth is effective in the prevention of classic HDN .
  Either intramuscular or oral ( 1.0 mg ) vitamin K prophylaxis improves biochemical indices of coagulation status at 1 - 7 days .
  Neither intramuscular nor oral vitamin K has been tested in r and omized trials with respect to effect on late HDN .
  Oral vitamin K , either single or multiple dose , has not been tested in r and omized trials for its effect on either classic or late HDN
background: BACKGROUND  Vitamin K deficiency can cause bleeding in an infant in the first weeks of life .
  This is known as Hemorrhagic Disease of the Newborn ( HDN ) .
  HDN is divided into three categories : early , classic and late HDN .
  Early HDN occurs within 24 hours post partum and falls outside the scope of this review .
  Classic HDN occurs on days one to seven ; common bleeding sites are gastrointestinal , cutaneous , nasal and from a circumcision .
  Late HDN occurs from week 2 - 12 ; the most common bleeding sites are intracranial , cutaneous , and gastrointestinal .
  Vitamin K is commonly given prophylactically after birth for the prevention of HDN , but the preferred route is uncertain .
  OBJECTIVES To review the evidence from r and omized trials in order to determine the effectiveness of vitamin K prophylaxis in the prevention of classic and late HDN .
  Main questions are : Is one dose of vitamin K , given after birth , able to significantly reduce the incidence of classic and late HDN ?
  Is there a significant difference between the oral route and the intramuscular route in preventing classic and late HDN ?
  Are multiple oral doses of vitamin K , given after birth , able to significantly reduce the incidence of classic and late HDN ?