PEDIATRICS Vol. 108 No. 5 November 2001, pp. 1117-1122

Vitamin K Status of Premature Infants: Implications for Current Recommendations

Deepak Kumar, MD, MRCP^*, Frank R. Greer, MD, Dennis M. Super, MD, MPH^*, John W. Suttie, PhD^§, and John J. Moore, MD^*

From the ^* Department of Pediatrics, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio; and the Departments of  Pediatrics and Nutritional Sciences and ^§ Biochemistry and Nutritional Sciences, University of Wisconsin, Madison, Wisconsin.

	ABSTRACT

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Objective.  Newborn infants are vitamin K deficient. Vitamin K status in full-term infants after intramuscular vitamin K supplementation at birth has been described. Similar information in growing premature infants has not been reported. The objective of this study was to assess vitamin K status in premature infants by measuring plasma vitamin K and plasma protein-induced in vitamin K absence (PIVKA II) from birth until 40 weeks' postconceptional age.

Methods.  Premature infants (36 weeks' gestation) were divided at birth into groups by gestational age (group 1, 28 weeks; group 2, 29-32 weeks; group 3, 33-36 weeks). Supplemental vitamin K (1 mg intramuscularly) was administered at birth followed by 60 µg/day (weight <1000 g) or 130 µg/day (weight 1000 g) via total parenteral nutrition. After hyperalimentation, most received vitamin K-fortified enteral feedings with the remainder receiving unfortified breast milk. Blood was obtained for PIVKA II in cord blood and for PIVKA II and vitamin K at 2 weeks and 6 weeks after birth and at 40 weeks' postconception.

Results.  Of the 44 infants enrolled, 10 infants in each gestational age group completed the study. The patient characteristics for groups 1, 2, and 3 were as follows: gestational age, 26.3 ± 1.7, 30.3 ± 1.3, and 33.9 ± 1.1 weeks; birth weight, 876 ± 176, 1365 ± 186, and 1906 ± 163 g; and days of hyperalimentation, 28.9 ± 16, 16.8 ± 12, and 4.3 ± 4 days, respectively. At 2 weeks of age, the vitamin K intake and plasma levels were highest in group 1 versus group 3 (intake: 71.2 ± 39.6 vs 13.4 ± 16.3 µg/kg/day; plasma levels: 130.7 ± 125.6 vs 27.2 ± 24.4 ng/mL). By 40 weeks' postconception, the vitamin K intake and plasma levels were similar in all 3 groups (group 1, 2, and 3: intake, 11.4 ± 2.5, 15.4 ± 6.0, and 10.0 ± 7.0 µg/kg/day; plasma level, 5.4 ± 3.8, 5.9 ± 3.9, and 9.3 ± 8.5 ng/mL). None of the postnatal plasma samples had any detectable PIVKA II.

Conclusions.  Premature infants at 2 weeks of age have high plasma vitamin K levels compared with those at 40 weeks' postconceptional age secondary to the parenteral administration of large amounts of vitamin K. By 40 weeks' postconception, these values are similar to those in term formula-fed infants. Confirming "adequate vitamin K status," PIVKA II was undetectable by 2 weeks of life in all of the premature infants. With the potential for unforeseen consequences of high vitamin K levels, consideration should be given to reducing the amount of parenteral vitamin K supplementation in the first few weeks of life in premature infants.vitamin K, PIVKA II, premature, total parenteral nutrition, enteral nutrition.

All newborn infants are relatively vitamin K deficient in the first few months of life.^1-4 Prenatal supplementation with vitamin K has little effect on umbilical cord blood vitamin K levels.^35-7 Vitamin K deficiency may cause life-threatening bleeding as a result of inadequate activity of vitamin K-dependent coagulation factors (II, VII, IX, and X), correctable by vitamin K replacement. Vitamin K deficiency also results in the secretion of undercarboxylated (abnormal) prothrombin into the plasma, called protein-induced in vitamin K absence or antagonism (PIVKA II).^8-10 Because breast milk is very low in vitamin K compared with standard formulas,^4,11 vitamin K deficiency is a particular problem in exclusively breastfed infants. Because of the risk of bleeding from vitamin K deficiency, all infants receive vitamin K prophylaxis (0.5-1.0 mg intramuscularly [IM]) at birth. This is efficacious for term infants, but no studies have provided similar data on preterm infants. The US Recommended Dietary Allowances committee recommends a vitamin K intake of 1 µg/kg/day for term infants after birth.¹² For premature infants, recommendations are arbitrary and range from 5 to 10 µg/kg/day¹³ to as high as 100 µg/kg/day.¹⁴ Recently, vitamin K status and ways to improve it have been reported in healthy term infants.^8,15 Similar data are not available for premature infants. Our aim was to assess vitamin K status of premature infants by measuring plasma vitamin K concentrations and PIVKA II concentrations from birth until 40 weeks' postconceptional age.

	METHODS

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Patient Selection

Premature infants who were born at the MetroHealth Medical Center (MHMC) at 36 weeks' gestation and whose birth weight was appropriate for gestation were included in the study. Infants with life-threatening congenital anomalies, uncertainty of gestational age, administration of fresh-frozen plasma within the week before blood sampling, multiple gestation (>2; for twin births, only 1 infant enrolled), or antenatal exposure to anticonvulsants or antituberculosis agents were excluded. Mothers who were admitted to the labor and delivery unit for premature delivery were identified and were approached by the principle investigator to participate in the study. When the parents of a premature infant declined to participate in the longitudinal study, all patient identifiers (except gestational age, gender, and race) were removed from the cord blood sample. This study was approved by the Human Subject Committee of the Institutional Review Board at MHMC. Informed written consent was obtained from parents of all of the infants enrolled in the study. Patients were enrolled until 30 premature infants (10 for each of the gestational age groups) completed the study. The gestational age groups were defined a priori as group 1 (28 weeks), group 2 (29-32 weeks), and group 3 (33-36 weeks).

Vitamin K Supplementation

All of the premature infants received 1 mg of vitamin K IM at birth per policy in the neonatal intensive care unit (NICU) at MHMC. Postnatal parenteral vitamin K supplementation was provided through total parenteral nutrition (TPN), using standard multivitamin mixture (MVI-Pediatric, Astra Pharmaceuticals, Westborough, MA) to provide 60 µg/day to infants who weighed <1000 g and 130 µg/day to infants who weighed 1000 to 3000 g. Vitamin K content of Intralipid 20% IV Fat Emulsion (Fresenius Kabi Nutrition AB, Clayton, NC) varies from lot to lot and ranges from 200 to 700 µg/L (Diane Nitzki-George, Clinitec Nutrition Division, Baxter Healthcare Corporation, personal communication, October 2000).^16-19 For the purpose of calculating vitamin K intake from the infused standard Intralipid 20% IV Fat Emulsion, we used vitamin K concentration of 300 µg/L (Diane Nitzki-George, Clinitec Nutrition Division, Baxter Healthcare Corporation, personal communication, October 2000). Enteral vitamin K intake was provided by commercial premature formula (65-100 µg/L),²⁰ fortified maternal breast milk (MBM; 45-49 µg/L),²⁰ or unfortified MBM (2 µg/L).⁴ In the NICU, the amount and type of nutrition for 3 consecutive days before a blood sampling was recorded. After discharge, the parents maintained a feeding record at home for 3 days before the scheduled visit for blood sampling and weight measurement. For breastfed infants, the amount per feeding was calculated from the difference in the infant's weight before and after a feeding on the day of the blood sampling. This amount was then multiplied by the number of breastfeedings per day to calculate daily breast milk intake. The average daily vitamin K intake for that period was calculated by multiplying the average volume received for those 3 days by the known concentrations of vitamin K for each type of nutrition.

Blood Collection

Blood (2 mL) was obtained in lithium heparin containers at birth (cord), 2 weeks (±2 days), 6 weeks (±4 days), and at term (40 ± 2 weeks' postconceptional age). As the infants in group 3 would be term at 6 weeks of age, the results from their 6-week phlebotomy are reported as 40 weeks' postconceptional age rather than 6 weeks of age. The blood samples were centrifuged for 5 minutes at 2100 × g at 4°C. The plasma was then split into 2 aliquots and stored at 70°C.

Vitamin K Assay

Vitamin K was assayed in plasma by a modification of a previously described multistage procedure.²¹ After extraction of 0.5 mL of plasma with hexane, the lipid extract was purified by normal-phase high-performance liquid chromatography and analyzed with reversed-phase high-performance liquid chromatography using electrochemical detection in the redox mode. Menaquinone-6 was used as the internal standard. The lower limit of detection was 0.05 ng/mL. The mean plasma vitamin K concentration of healthy fasting adults is 0.5 ng/mL.^15,22 Individuals who conducted the vitamin K assays were blinded to the gestational age and type of nutrition that the infants were receiving.

PIVKA II Assay

The PIVKA II assay was performed on plasma using a murine monoclonal antibody available in an enzyme immunoassay kit (Asserachrom PIVKA-II; Diagnostica-Stago, Asnieres Sur Seine, France). The normal value for PIVKA II in adults is <2 ng/mL with this method.²³ Individuals who conducted the PIVKA II assays were blinded to the gestational age and type of nutrition that the infants were receiving.

Statistics

Interval data are reported as mean ± standard deviation. Kruskal-Wallis 1-way analysis of variance was used to determine the differences among the 3 groups for interval data. When the P value was < .05, posthoc Mann-Whitney U test was performed with the Bonferroni adjustment for reducing test-wise error. The Wilcoxon matched-pairs signed-ranks test was used for paired interval level data. Statistical significance was defined a priori as a P < .05 (2-tail). Data were analyzed with SPSS for Windows V9.0 (SPSS Inc, Chicago, IL).

	RESULTS

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Patient Characteristics

Between December 1997 and June 1999, 71 infants were identified as eligible candidates for the study. Forty-four infants were enrolled, 30 of whom completed the study. One infant who was born at 33 weeks' gestation died at 2 weeks of age in the NICU. The remaining 13 infants were lost to follow-up. Two of these infants had blood drawn at 2 and 6 weeks of age but not at 40 weeks' postconceptional age. Hence, they were excluded from the study. One (34 weeks' gestation) was readmitted to the pediatric intensive care unit with respiratory syncytial virus infection at 2 weeks of age, and parents refused blood draw. Ten infants (33-36 weeks' gestation) did not show for appointment despite reminders 3 days before scheduled visits. Patients in each of the 3 groups were similar with regard to race and gender. However, the infants in groups 1 and 2 versus 3 had more days of TPN (Table 1).

Postnatal Vitamin K Supplementation

At 2 weeks of age, the vitamin K supplementation was higher in the more premature infants (group 1 vs 3; P < .05). By 40 weeks' postconceptional age, it was similar among all groups (Table 2). At 2 weeks, the higher vitamin K supplementation in the more premature infants was secondary to more of these infants receiving TPN (group 1: 80%; group 3: 12.5%). By 40 weeks' postconceptional age, all infants were fed enterally (Table 3).

Plasma Vitamin K Concentrations

At 2 weeks of age, the vitamin K levels were highest in group 1 (Table 4). In each of the 3 groups, the vitamin K levels decreased significantly (P < .05) from 2 weeks to 40 weeks' postconceptional age. By 40 weeks' postconceptional age, the vitamin K levels were similar among all groups (Table 4). The lowest individual vitamin K concentration obtained in our study was 0.8 ng/mL. Hence, all infants exceeded 0.5 ng/mL, the mean normal vitamin K concentration in healthy fasting adults.

Plasma Vitamin K Concentration in Relation to Nutrition

At 2 weeks of age, parenteral nutrition resulted in higher plasma vitamin K levels than enteral nutrition (Table 5). By 40 weeks' postconception, all of the infants who had initially received TPN were exclusively enterally fed. At term, their plasma vitamin K levels were similar to those who received enteral feedings only at 2 weeks.

Only 4 infants (group 3) received unfortified MBM for any significant duration (mean vitamin K intake: 0.4 µg/kg/day). One infant received TPN for the first 8 days of life followed by only unfortified MBM until term. This infant had plasma vitamin K levels of 16.9 ng/mL and 0.8 ng/mL at 2 weeks and term, respectively. The second received unfortified MBM until 2 weeks of age followed by vitamin K-fortified MBM and formula. This infant had a plasma vitamin K level of 8.8 ng/mL at term. The third infant had a vitamin K level of 1.31 ng/mL at term after 5 weeks of unfortified MBM. The fourth infant (born at 36 weeks), who was fed unfortified MBM exclusively since birth, had a vitamin K level of 1.4 ng/mL 2 weeks after birth.

PIVKA II

PIVKA II was detectable in 19 (27.5%) of 69 cord blood samples that were available for assay. If PIVKA II of <10 ng/mL is considered normal for newborn infants, then 14 (20.3%) of 69 had values 10 ng/mL. There was no difference in the incidence of detectable PIVKA II in cord blood for gender, race, and gestational age. Of the 30 infants who were followed longitudinally, 9 of the available 28 cord blood samples had detectable PIVKA II. With vitamin K supplementation, none of their postnatal samples at 2, 6, and 40 weeks had any detectable PIVKA II.

	DISCUSSION

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Published guidelines for vitamin K supplementation are specific for all ages except for premature infants.¹² There are no published data regarding the appropriateness and adequacy of current recommendations for vitamin K supplementation of premature infants. Our study begins to address these issues.

The plasma vitamin K concentrations were high in premature infants at 2 weeks of age, especially in those who were receiving multivitamins in TPN solutions. This reflects high amounts of vitamin K given IM at birth and subsequently through parenteral nutrition. Premature infants (24-36 weeks) in our study had much higher vitamin K plasma concentrations at 2 and 6 weeks of age than that documented in the literature in healthy, term, formula-fed infants (4-6 ng/mL).⁴ By 40 weeks, when all infants were enterally fed, the mean plasma vitamin K concentrations in all groups were similar to those of healthy, term, formula-fed infants during the first 6 months of life.⁴ Sann et al²⁴ documented a plasma vitamin K concentration of 310 ng/mL in 10 low-birth-weight infants with mean gestation of 35 to 36 weeks at 24 hours of age after 2 mg of vitamin K orally. In term infants, Greer et al³ documented plasma vitamin K concentrations of 21 ng/mL in healthy breastfed infants and 27.5 ng/mL in healthy formula-fed infants at day of life 5 after 1 mg of vitamin K IM at birth. In both of these studies, the vitamin K levels reflect the amounts of vitamin K given at birth. At all times, plasma vitamin K concentrations in our preterm infants, irrespective of their gestation and route of vitamin K supplementation, were higher than that of healthy fasting adults (0.5 ng/mL). The unfortified MBM-fed infants with plasma vitamin K concentrations of 1.4 ng/mL at 2 weeks of age reflect the persisting high vitamin K levels after large dose of vitamin K (1 mg IM) at birth.

Our study confirmed the high reported incidence of detectable PIVKA II (10%-50%) in cord blood.^22,25 PIVKA II was detected in 27.5% of the premature (69) cord blood samples assayed. There was no relationship between PIVKA II concentrations in cord blood and gestation, race, or gender. If <10 ng/mL is considered normal, then 14 (20.28%) premature cord blood samples were abnormally elevated for PIVKA II. The only other published study of PIVKA II measurements in premature cord blood included 13 premature (27-36 weeks) and 46 term (37-41 weeks) cord blood samples. The presence of elevated cord PIVKA II (10 ng/mL) in 31 of their 57 (52%) infants was unrelated to their gestational age.²⁶ Although cord blood samples have almost undetectable vitamin K levels at birth, it is uncertain why only 20% of our premature infants had elevated PIVKA II levels. Reassuring is that all measurements done in the 30 premature infants postnatally at 2 and 6 weeks of age and 40 weeks' postconception contained no detectable PIVKA II, confirming adequate vitamin K status also confirmed by the vitamin K concentrations in their plasma.

In this population of premature infants who were 36 weeks' gestation, the vitamin K intakes were comparable to the current recommendations. Recommended vitamin K intakes of parenterally fed premature infants vary (2-100 µg/day¹⁴ to 80 µg/day²⁷). Infants who received any parenteral nutrition at 2 weeks of age had a vitamin K intake (84.2 µg/day) similar to that recommended (80 µg/day) by the American Academy of Pediatrics Pediatric Nutrition Handbook.²⁷ Infants exclusively enterally fed had intakes similar to those recommended by the American Academy of Pediatrics (6-9 µg/kg/day) for growing preterm infants.^13,27 This is also similar to vitamin K intakes of term formula-fed infants during the first 6 months of life.⁴ For most patients, the vitamin K intake was higher at 2 weeks secondary to supplementation with parenteral nutrition. In fact, the premature infants who received the highest intakes of intravenous nutrition received the largest intake of vitamin K. By 40 weeks, when all infants were exclusively enterally fed, vitamin K intake was similar in all groups. Exclusively MBM-fed infants received significantly less vitamin K, 0.41 µg/kg/day, which is less than the US Recommended Dietary Allowances Committee recommendation (1 µg/kg/day) for all ages but similar to vitamin K intakes of term, healthy, breastfed infants through the first 6 months of life.⁴

One limitation of our study, which started in 1997, is that all study infants received 1 mg of vitamin K IM at birth according to our NICU policy, which is the upper limit of the current recommendation (0.5-1.0 mg).²⁷ This dose was concurrent with the former recommendations of the American Academy of Pediatrics.²⁸ Revised recommendations for premature infants with birth weight of <1000 g are 0.3 mg/kg IM and became available in 1998.²⁷ Only 8 of 30 premature infants in our study had a birth weight of <1000 g. Data from our unfortified MBM-fed infants suggest that 1 mg of vitamin K IM at birth is adequate at 2 weeks of age, even in MBM-fed infants. For the infants who received large amounts of vitamin K through TPN (81 µg/kg/day; Table 5), the plasma vitamin K levels are high (124 ng/mL). It is of note that children and adults on parenteral nutrition may maintain adequate vitamin K status from 20% Intralipid infusion alone because it contains a significant amount of vitamin K (200-700 µg/L; Diane Nitzki-George, Clinitec Nutrition Division, Baxter Healthcare Corporation, personal communication, October 2000).^16-19,29 Accordingly, premature infants may receive a significant (1-3.5 µg/kg/day) portion of total daily recommended vitamin K from 1 g/kg of 20% Intralipid infusion. It has been suggested that 10 µg/kg/day vitamin K via TPN would be more than adequate for premature infants.¹³ This amount would approximate the vitamin K intake of formula-fed infants, which is known to prevent vitamin K deficiency bleeding.¹³ Presently, an appropriate intravenous multivitamin parenteral preparation that could provide the suggested reduced amount (10 µg/kg/day) of vitamin K is not available.

We are unsure of the risks to premature infants resulting from the supraphysiologic levels of vitamin K. In the past, high doses of a water-soluble vitamin K (menadione) preparation were associated with red cell hemolysis and hyperbilirubinemia, leading to kernicterus in the premature infants.³⁰ Fat-soluble vitamin K (phylloquinone) preparation has been used for the past 4 decades without any associated hemolysis even when given in large doses. In 1992, Golding et al³¹ questioned the safety of prophylactic intramuscular vitamin K at birth and reported an associated increased rate of childhood cancer. This study had several limitations. Several large population studies refute these findings.^32-40 Limited basic science data implicating vitamin K in causing increased sister chromatid exchanges in human and animal lymphocytes is contradictory.^41,42 Both the American and the Canadian pediatric societies have reaffirmed their confidence in intramuscular vitamin K prophylaxis.^28,43

	CONCLUSION

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Vitamin K levels in premature infants directly reflect vitamin K intakes. With current vitamin K supplementation, premature infants at 2 weeks of age have high levels of plasma vitamin K secondary to 1 mg of intramuscular vitamin K administration at birth and the high amount of vitamin K in parenteral nutrition multivitamins. These levels decline by 40 weeks' postconceptional age, when infants are enterally fed, at which time they are comparable to term, formula-fed infants. Confirming adequate vitamin K status and vitamin K supplementation, PIVKA II is undetectable by 2 weeks of life. In our population of premature infants of <37 weeks' gestation, the vitamin K intakes were consistent with the current recommended wide range of guidelines (from 5-100 µg/kg/day) for premature infants. However, current vitamin K supplementation of premature infants, particularly at 2 weeks, provides excessive amounts of vitamin K. Although not apparent in this study, this has a potential for unforeseen side effects. Optimal vitamin K requirements of premature infants are undefined, but present evidence suggests that parenteral vitamin K supplementation in the first few weeks of life should be reduced.

	ACKNOWLEDGMENTS

This study was funded in part by the General Clinical Research Center (GCRC) Grant from NIH (MO1RR00080) awarded to MetroHealth Medical Center and the American Bioproducts Company/Stago, which kindly provided PIVKA II kits.

Presented in part at the Pediatric Academic Societies and American Academy of Pediatrics Joint Meeting in Boston, Massachusetts, May 12-16, 2000.

We thank Susan Hochevar, Sara Gagnon, and other nurses in the GCRC and the NICU for their diligence, patience, and assistance with this project. We are also grateful to the parents and their premature infants for participating in the study.

	FOOTNOTES

Received for publication Nov 29, 2000; accepted Apr 17, 2001.

Reprint requests to (D.K.) Department of Pediatrics, MetroHealth Medical Center, 2500 MetroHealth Dr, Cleveland, OH 44109. E-mail: dkumar{at}metrohealth.org

	ABBREVIATIONS

PIVKA II, protein-induced in vitamin K absence or antagonism; IM, intramuscularly; NICU, neonatal intensive care unit; TPN, total parenteral nutrition; MBM, maternal breast milk.

	REFERENCES

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1. Von Kries R, Shearer MJ, Göbel U Vitamin K in infancy. Eur J Pediatr. 1988; 147:106-112 [CrossRef][Medline]
2. Von Kries R, Göbel U Vitamin K prophylaxis and vitamin K deficiency bleeding in early infancy. Acta Pediatr 1992; 81:655-657 [Medline]
3. Greer FR, Mummah-Schendel LL, Marshall S, Suttie JW Vitamin K₁ and vitamin K₂ status in the newborn during the first week of life. Pediatrics 1988; 81:137-140 [Abstract/Free Full Text]
4. Greer FR, Marshall S, Cherry J, Suttie JW Vitamin K status of lactating mothers, human milk and breast feeding infants. Pediatrics 1991; 88:751-756 [Abstract/Free Full Text]
5. Mandelbrot L, Guillaumont M, Leclercq M, Placental transfer of vitamin K₁ and its implications in fetal hemostasis. Thromb Haemost 1988; 60:39-43 [Medline]
6. Pietersma-de Bruyn AL, Van Haard PM Vitamin K₁ in the newborn. Clin Chim Acta 1985; 150:95-101 [CrossRef][Medline]
7. Shearer MJ, Barkhan P, Rahim S, Stimmler L Plasma vitamin K₁ in mothers and their newborn babies. Lancet 1982; 1:460-463 [Medline]
8. Von Kries R, Greer FR, Suttie JW Assessment of vitamin K status of the newborn infant. J Pediatr Gastroenterol Nutr 1993; 16:231-238 [Medline]
9. Hemker HC, Vellkamp JJ, Hensen A, Loeliger ER Nature of prothrombin biosynthesis: preprothrombinaemia in vitamin K deficiency. Nature 1963; 200:589 [CrossRef][Medline]
10. Ganrot PO, Nilehn JE Plasma prothrombin during treatment with Dicumarol II. Demonstration of an abnormal prothrombin fraction. Scand J Clin Lab Invest 1968; 22:23-28 [Medline]
11. Bolisetty S, Gupta JM, Graham GG, Salonikas C, Naidoo D Vitamin K in preterm breastmilk with maternal supplementation. Acta Paediatr 1998; 87:960-962 [CrossRef][Medline]
12. Food and Nutrition Board, Commission on Sciences, National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1988:111
13. Greer FR. Vitamin K. In: Tsang RC, Lucas A, Uauy R, Zlotkin S, eds. Nutritional Needs of the Preterm Infant: Scientific Basis and Practical Guidelines. Baltimore, MD: Williams & Wilkins; 1993:111-119
14. Greene H, Hambridge K, Schanler R, Tsang RC Guidelines for the use of vitamins, trace elements, calcium, magnesium and phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Nutrition. Am J Clin Nutr 1988; 48:1324-1342 [Free Full Text]
15. Greer FR, Sharon P, Marshall S, Foley AL, Suttie JW Improving the vitamin K status of breastfeeding infants with maternal vitamin K supplements. Pediatrics 1997; 99:88-92 [Abstract/Free Full Text]
16. Goulet O, Lefrere JJ, Guillalmont M, An unknown source of vitamin K₁ in patients on total parenteral nutrition. Clin Nutr 1990; 9:85-87
17. Chambrier C, Leclercq M, Saudin F, Is vitamin K₁ supplementation necessary in long-term parenteral nutrition? JPEN J Parenter Enteral Nutr 1998; 22:87-90 [Abstract/Free Full Text]
18. Lennon C, Davidson KW, Sadowski JA, Mason JB The vitamin K content of intravenous lipid emulsions. JPEN J Parenter Enteral Nutr 1993; 17:142-144 [Abstract/Free Full Text]
19. Drittij-Reijnders MJ, Sels JP, Rouflart M, Thijssen HH Vitamin K status and parenteral nutrition: the effect of Intralipid on plasma vitamin K₁ levels. Eur J Clin Nutr 1994; 48:525-527 [Medline]
20. Ross Pediatrics. Composition of feedings for infants and young children. In: Ross Ready Reference. Columbus, OH: Ross Products Division, Abbott Laboratories Inc; 1999
21. Haroon Y, Bacon DS, Sadowski JA Liquid-chromatographic determination of vitamin K₁ in plasma with fluorometric detection. Clin Chem 1986; 32:1925-1929 [Abstract/Free Full Text]
22. Greer FR, Marshall SP, Severson RR, A new mixed-micellar preparation for oral vitamin K prophylaxis: randomized controlled comparison with an intramuscular formulation in breast-fed infants. Arch Dis Child 1998; 79:300-305 [Abstract/Free Full Text]
23. Admiral J, Grosley M, Plassart V, Mimilla F, Chambrette B Development of a monoclonal immunoassay for the direct measurement of descarboxyprothrombin of plasma [abstract]. Thromb Haemost 1991; 65:648
24. Sann L, Leclercq M, Guillaumont M, Trouyez R, Bethenod M, Bourqeay-Causse M Serum vitamin K₁ concentrations after oral administration of vitamin K₁ in low birth weight infants. J Pediatr 1985; 4:608-611
25. Bovill EG, Soll RF, Lynch M, Vitamin K₁ metabolism and the production of descarboxy prothrombin and protein C in the term and premature neonate. Blood 1993; 81:77-83 [Abstract/Free Full Text]
26. Greer FR, Costakos DT, Suttie JW Determination of des-gamma-carboxy-prothrombin (PIVKA II) in cord blood of various gestational ages with the STAGO antibody: a marker of vitamin k deficiency? [abstract]. Pediatr Res 1999; 45:283A
27. American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of preterm infants. In: Pediatric Nutrition Handbook. 4th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1998:55-87
28. American Academy of Pediatrics, Vitamin K Ad Hoc Task Force Controversies concerning vitamin K and the newborn . Pediatrics 1993; 91:1001-1003 [Abstract/Free Full Text]
29. Pettei MJ, Israel D, Levine J Serum vitamin K concentration in pediatric patients receiving total parenteral nutrition. JPEN J Parenter Enteral Nutr 1993; 17:465-467 [Abstract/Free Full Text]
30. Allison AC Danger of vitamin K to newborn [letter]. Lancet 1955; 1:669
31. Golding J, Greenwood R, Birmingham K, Mott M Childhood cancer, intramuscular vitamin K, and pethidine given during labour. Br Med J 1992; 305:341-346
32. Ekelund H, Finnstrom O, Gunnarskog J, Kallen B, Larsson Y Administration of vitamin K to newborn infants and childhood cancer. Br Med J 1993; 307:89-91
33. Klebanoff MA, Reads JS, Mills JL, Shino PH The risk of childhood cancer after neonatal exposure to vitamin K. N Engl J Med 1989; 329:905-908 [Abstract/Free Full Text]
34. Olsen JH, Hertaz H, Blinkenberg K, Verder H Vitamin K regimens and incidence of childhood cancer in Denmark. Br Med J 1994; 308:895 [Free Full Text]
35. Von Kreis R, Gobel U, Hachmeister A, Kaletsh U, Michaelis J Vitamin K and childhood cancer: a population based case-control study in Lower Saxony, Germany. Br Med J 1996; 313:199-203 [Abstract/Free Full Text]
36. Ansell P, Bull D, Roman E Childhood leukemia and intramuscular vitamin K: findings from a case-control study. Br Med J 1996; 313:204-205 [Free Full Text]
37. McKinney PA, Juszczak E, Findlay E, Smith K Case-control study of childhood leukemia and cancer in Scotland: findings for neonatal intramuscular vitamin K. Br Med J 1998; 316:173-177 [Abstract/Free Full Text]
38. Passmore SJ, Draper G, Brownbill P, Kroll M Ecological studies of relationship between hospital policies on neonatal vitamin K administration and subsequent occurrence of childhood cancer. Br Med J 1998; 316:184-189 [Abstract/Free Full Text]
39. Passmore SJ, Draper G, Brownbill P, Kroll M Case-control studies of relation between childhood cancer and neonatal vitamin K administration. Br Med J 1998; 316:174-184
40. Parker L, Cole M, Craft W, Hey EN Neonatal vitamin K administration and childhood cancer in north of England: retrospective case-control study. Br Med J 1998; 316:189-193 [Abstract/Free Full Text]
41. Cornelissen EAM, Smeets D, Merkx G, De Abreu R, Kolle L, Monnens L Analysis of chromosome aberrations and sister chromatid exchanges in peripheral blood lymphocytes of newborns after vitamin K prophylaxis at birth. Pediatr Res 1991; 30:550-553 [Medline]
42. Israels LG, Friesen E, Jansen AH, Israels ED Vitamin K1 increases sister chromatid exchange in vivo in fetal sheep cells: a possible role for "vitamin K deficiency" in the fetus. Pediatr Res 1987; 22:405-408 [Medline]
43. Canadian Paediatric Society Routine administration of vitamin K to newborns. Joint position paper of the Canadian Paediatric Society and the Committee on Child and Adolescent Health of the College of Family Physicians of Canada. Can Fam Physician 1998; 44:1083-1090 [Medline]