Personal Practice

INDIAN PEDIATRICS VOLUME 34-AUGUST 1997

Personal Practice

Vitamin K During Infancy: water soluble and has the potential risk of Current Status and producing serious jaundice in newborn Recommendations babies especially those with instability of glutathione and deficiency of G6 PD. Vi- tamin K is absorbed through the jejunum and ileum with the help of bile and pancre- Meharban Singh atic juice. In newborn babies, around 30% of ingested vitamin K is absorbed as com- pared to 50 to 70% in adults. It is believed that plasma half life of vitamin K is less Vitamin K is usually the first vitamin than 72 hours but it may be stored in the given at birth. Dietary deficiency of vita- healthy liver for upto one month. The half min K in healthy subjects is rare because it life of prothrombin is only for few hours. is indigenously produced in the gut by Daily requirement of vitamin K is around 5 bacterial flora. In clinical practice, deficien- µg/d and an intake of around 10 µg/d is cy of micro-nutrients usually occur in vari- sufficient to provide for daily needs. Blood ous combinations but vitamin K deficiency PIVKA II (protein induced in vitamin K though rare, often occurs in an isolated absence) is an excellent marker of vitamin form. Vitamin K is essential for synthesis of K deficiency. Hemorrhagic disease of the coagulation factors II (prothrombin), VII, newborn, which is a manifestation of IX and X by a process of carboxylation of vitamin K deficiency in a newborn baby, is glutamic acid in vitamin K-dependent pro- conventionally suspected by prolonged teins which results in creation of effective partial thromboplastin time and prothrom- calcium binding sites which helps in the bin time. These laboratory abnormalities process of coagulation. Vitamin K exists in are also seen in patients with disseminated three forms: naturally occuring vitamin K-I intravascular coagulation (DIC) but in DIC, (Phylloquinone) which is provided through factor V, fibrinogen and platelets are also dietary sources like green leafy vegetables low and there are circulating fibrin degra- (50-800 (ig/100 g) and vegetable oils; vita- dation products in the blood. min K-II (menaquinone) which is indigenously produced in the gut by bacteroides Hemorrhagic Disease of the Newborn fragilis and E. coli and synthetic vitamin K- III (menadoine sodium bisulfite) which is The term hemorrhagic disease of the newborn (HDN) was first used in 1894 From the Department of Pediatrics, WHO when Townsend(l) reported 50 infants collaborating center for Training and Research with bleeding manifestations during the in Newborn Care, All India Institute of Medical first 2 weeks of life. Hemorrhagic disease of Sciences, New Delhi 110 029. the newborn is the commonest manifesta- Reprint requests: Dr. Meharban singh, Professor tion of vitamin K deficiency in infancy. On and Head, Department of Pediatrics, All India the basis of age of onset, there are three Institute of Medical Sciences, Ansari Nagar, types of hemorrhagic disease of the new- New Delhi 110 029. born:

708 INDIAN PEDIATRICS VOLUME 34-AUGUST 1997

(a)Early HDN vitamin K requirements due to ineffective Onset is usually during first 24 hours of vitamin K-I epoxide reductase system may life. Fetal hemorrhage and early HDN is be responsible for some cases(4,5). limited to offsprings of mothers receiving anticonvulsants, antituberculous agents, Should Healthy Breastfed Neonates be coumarin derivatives, salicylates, etc. dur- Given Vitamin K Supplementation at ing pregnancy. Birth? (b) Classical HDN Transplacental passage of vitamin K is It has onset between 1-7 days of life and minimal with maternal to cord blood vita- is usually limited to exclusively breastfed min K ratio of 30:1. Hepatic content of vita- infants. The common clinical manifesta- min K in a neonate is 25% of an adult. It is tions include bleeding from umbilical believed that precarious coagulation status stump and gastrointestinal tract. Its report- of a newborn baby may be further jeopar- ed incidence in the literature varies be- dized by breastfeeding because vitamin K tween 0.25-0.5% while our own observa- content of human milk (15 Mg/1) is one- tions and data by Jelliffe(2) suggests that fourth of cow's milk. Moreover, exclusively it's incidence is around 0.1% in breastfed breastfed babies are often starved during babies. first three days of life due to insufficiency (c) Late HDN of lactation. On the basis of these observa- tions, The American academy of Pediatrics It has onset between 1-16 weeks of life. recommended in 1961 that all healthy term It is rare in top fed infants and in infants newborn babies should receive 0.5-1.0 mg who had received injectable vitamin K at vitamin K-I intramuscularly at birth(6). birth. Its incidence is reported to be around However, these recommendations are not one in 14,000 infants when no vitamin K uniformly accepted and adopted because prophylaxis is used at birth. In a nation many workers do not routinely give pro- wide survey conducted in Germany by phylactic vitamin K at birth to healthy term Dusseldorf, it has been documented that babies. when vitamin K is administered parenter- ally at birth, incidence of late HDN drops We have not followed the recommenda- to 1:4,20,00 population(3). Intracranial tions of American Academy of Pediatrics in bleeding is seen in over 50% cases of late- our Neonatal Unit for the past 15 years(7). There are numerous biological advantages onset HDN which carries a relatively of human milk and despite the available high mortality and high incidence of scientific evidence pertaining to HDN, it is neuromotor sequelae among the difficult to comprehend that healthy term survivors. Most cases of late HDN are babies fed on breastmilk are predisposed to idiopathic. It may occur following develop classical HDN. It is against the prolonged use of broad basic principles of nature and common- spectrum antibiotic therapy, chronic diar- sense that a readymade food produced by rhea and malabsorption. Cholestatic hepa- nature is deficient in an important nutrient titis due to diverse etiology may be associ- and is unable to serve the nutritional needs ated with late onset HDN due to malab- of a healthy baby(8). The incidence of clas- sorption of vitamin K from the gut. It sical HDN is merely 0.1% in our neonatal has been postulated that immaturity of car- unit. It is well known that colostrum boxylase system in the liver and increased has higher content of vitamin K and it is

709 PERSONAL PRACTICE ■ possible that vitamin K in the human milk healthy term babies. Most workers, howev- has enhanced bioavailability and absorp- er, recommend administration of 1.0-2.0 tion. Due to the common practice of giving mg vitamin K-I (phylloquinone) orally at prelacteal and prolacteal feeds, despite spe- birth. Water soluble vitamin K is easily ab- cific instructions against their use, it is pos- sorbed through the gut while fat soluble vi- sible that there is early colonization of gut tamin K requires bile salts for its absorp- in our babies resulting in reduced inci- tion. Vitamin K3 (menadione sodium dence of classical HDN. Moreover, oral bisulfite) is readily absorbed in the gut and preparation of vitamin K is not available in is effective in correcting vitamin K deficien- India and one would have to give 1000 in- cy(12,13). Some workers consider this rou- jections of vitamin K to prevent one case of tine prophylactic administration of vitamin classical HDN which can be easily diag- K to healthy term babies as unnecessary. nosed and promptly managed by therapeu- tic administration of vitamin K. There are Vitamin K in High Risk Newborn Babies logistic difficulties, inherent risks of intra- We are following a selective policy of muscular injections (sepsis, hepatitis B vi- giving prophylactic vitamin K 0.5-1.0 mg rus and HIV infections) and above all dan- IM to high risk newborn babies (Table I). ger of inadvertent administration of high dose of vitamin K-III (menadione sodium It is recommended that infants receiv- bisulphite available as 10 mg/ml in Indian ing total parenteral nutrition should be giv- market) which can lead to severe hemoly- en biweekly parenteral supplementation of sis, jaundice and even kernicterus. In view vitamin K and those receiving broad spec- of relatively high incidence of G6 PD defi- trum antibiotics should receive exogenous ciency in India, administration of synthetic vitamin K once a week because of steriliza- vitamin K to all newborn babies may have tion of the gut. In view of the fact that vita- a potential risk for occurrence of hemolytic min K is stored in the liver upto one month, jaundice. In view of the fact that plasma it would appear logical and desirable to ad- half life of vitamin K is only 72 hours and minister supplemental vitamin K parenter- its storage in a healthy liver is limited upto ally once a month till the high risk situation one month, it is difficult to comprehend resolves. that parenteral administration of one dose of vitamin K can prevent late-onset HDN Vitamin K in Infancy which may occur as late as 16 weeks (even Infants with prolonged diarrhea (more upto one year by some workers!). There is some controversial evidence that administration of vitamin K through intramuscular TABLE I- Indications for Giving Vitamin K to route may enhance the risk of cancer dur- High Risk Newborn Babies ing childhood(9). Two recent case control 1. High risk newborn babies: Preterm, <2.0 kg, studies have refuted the increased risk of traumatic delivery, birth asphyxia, grossly cancer in association with intramuscular SFD/LFD babies administration of vitamin K(10,11). 2. Maternal intake of coumarin derivatives (warfarin), anticonvulsants, salicylates and Despite its controversial status, the antituberculous drugs during pregnancy American Academy of Pediatrics recom- 3. Surgical neonate mends that 1.0 mg vitamin K should be ad- 4. Broad spectrum antibiotics ministered intramuscularly at birth to all 5. Total parenteral nutrition

710 INDIAN PEDIATRICS VOLUME 34-AUGUST 1997 than 2 weeks), malabsorption syndrome, during first week of life and at the age of 16 cholestatic hepatits and those receiving weeks in breastfed infants with or without prolonged broad spectrum antibiotics vitamin K supplementation at birth (oral should be given 1.0 mg vitamin K intra- and parenteral). There is a need to study muscular once every month or 50-100 µg the efficacy, safety and optimal dosage of daily. Breastfed infants of mothers receiv- orally administered synthetic vitamin K-III ing drugs which are known to cause vita- which is the only vitamin available in the min K dependent coagulation disorder, Indian market. Colonization of the gut should also be administered monthly sup- should be studied among exclusively plements of vitamin K(14). breastfed babies during first week of life. In order to reduce the incidence of late-onset In the light of available information in HDN, which is a potentially fatal and dis- the literature, the current recommendations abling disorder, it is desirable to study for prophylactic use of vitamin K to pre- whether oral supplementation of vitamin K vent HDN are summarized in Table II. to the mother during lactation can enhance vitamin K content of the breastmilk and Epilogue prevent occurrence of late HDN. It is hoped that ongoing research will provide In view of the current controversies and answers to the clinically relevant crucial lack of unanimity in the prophylactic use of questions that needs to be answered to en- vitamin K in early life, it is desirable to un- sure rational use of vitamin K during infan- dertake additional prospective studies to cy and childhood. In view of the efficacy of resolve some of the issues. Studies should oral vitamin K in correcting PIVKA-II ab- be undertaken to assess PIVKA-II levels 3 normalities(13), we have approached sev- TABLE II-Prophylaxis Regimens for Administra- eral pharmaceutical companies to market tion of Vitamin K vitamin K3 in an oral drops formulation in 10 ml dropper vials in a concentration of 1. Early HDN : Vitamin K 20 mg daily to 10 mg/m i.e. 0.5 mg/drop. Administration the high risk pregnant of two drops at birth to healthy term woman with potential babies should prevent classical HDN. risk of fetal hemorrhage Precise dosing of oral vitamin K for (those receiving anticonvulsants, antituberculous prevention of late-onset HDN also needs to agents, coumarin deriva- be studied. tives, salicylates) for 2 REFERENCES weeks before delivery. Vi- tamin K 1.0-2.0 mg IV to 1. Townsend CW. The hemorrhagic disease the baby at birth. of the newborn. Arch Pediatr 1894; 11: 2. Classical HDN : Vitamin K 0.5-1.0 mg IM 559-565. at birth (high risk group) 2. Jelliffe DB. Personal communication, Vitamin K 1.0-2.0 mg oral 1976. at birth (healthy term ba- 3. Kries RV, Becker A, Gobel U, Maase B. bies). Latent vitamin K deficiency in healthy in- 3. Late HDN : Vitamin K 1.0 mg IM at fants? Lancet 1985; 2:1421-1422. birth. Vitamin K 1.0 mg IM once every month or 4. Corrigan JJ, Taussing IM, Beckerman R, 50-100 µg daily supple- Wagener JS, Ariz T. Factor II Coagulant ments in high risk infants. activity and immuno-reactive protein:De- tection of vitamin K deficiency and liver

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disease in patients with cystic fibrosis. J 10. Krier RV, Gobel V, Hachmeister A, Pediatr 1981; 99: 254-257. ' Kaletsch U, Michaelis J. Vitamin K and childhood cancer: A population based 5. Lane PA Hathaway WE. Vitarnm K in m- case control study in Lower Saxony, Ger- fancy. J Pediatr 1985; 106: 351-359. many BMJ 1996;313:199-203. 6. Committee on Nutrition. American Acad- 11. Ansell P, Bull D, Roman E. Childhood emy of Pediatrics. Vitamin K compounds leukemia and intramuscular vitamin K: and the water soluble analogues: Use in Findings from a case control study. Brit therapy and prophylaxis in Pediatrics. Pe- Med J 1996; 313: 204-205. diatrics 1961, 28:501-506. 12. Naryanan I, Saili A, Khandara AL. Vita- 7. Singh M. Do breastfed healthy neonates min K for the newborn: Old avenues re- need vitamin K supplementation? Acade- visited. Indian Pediatr 1989; 26: 1229- my Today, April 1991, p 12. 1234. 8. Malia RG, Preston FE, Mitchell VE. Evi- 13. Bakhshi S, Deorari AK, Roy S, Paul VK, dence against vitamin K deficiency in nor- Singh M. Prevention of subclinical vita- mal neonates. Thromb Hemost 1980; 44: min K deficiency based on PIVKA II lev- 159-160. els: Oral versus intramuscular route. Indi- an Pediatr 1996; 33:1040-1043. 9. Golding J, Greenwood R, Birmingham K, Mott M. Childhood cancer, intramuscular 14. Kries RV, Shearer MJ, Globel U. Vitamin vitamin K and pethidine given during K in infancy. Eur J Pediatr 1988; 147:106- labour. Brit Med J 1992; 305: 341-346. 112.

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