Vitamin K in human milk--still not enough.

The breastfed infant has limited sources of vitamin K, as it is transmitted poorly across the placenta and is present in very low concentrations in human milk. The author of this paper reports a concentration of vitamin K in human milk (0.517 +/- 1.521 microg/dl) that is about twice the average of earlier reports (0.25 microg/dl). About half of the increased concentration (0.235 +/- 0.144 microg/dl) is accounted for by vitamin K2 (menaquinone) rather than vitamin K1 (phylloquinone); the latter generally thought to be more important in human nutrition. The significance of these findings is discussed.

Vitamin K status of premature infants: implications for current recommendations.

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 (/=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 microg/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 microg/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.

Do breastfed infants need supplemental vitamins?

Table 2 shows that human milk will not meet the DRI for all vitamins in breastfeeding infants. The most glaring discrepancy between intake and the RDA is for vitamin D, although, as discussed, infants may synthesize this from sunlight exposure. Vitamin K must be given in the newborn period. Deficiencies of other vitamins are rare, especially if mothers are nourished adequately. If breastfeeding infants are to be supplemented with vitamin D or any other vitamins, the standard liquid preparations available all contain large amounts of the water-soluble and fat-soluble vitamins (except for vitamin K), which more than meets the RDA. The milk content of thiamin, pyridoxine, and niacin is correlated highly with maternal intake, and these vitamins are all present in relatively large amounts in standard multivitamin tablets given to lactating mothers. In conclusion, in healthy, breastfed infants of well-nourished mothers, there is little risk for vitamin deficiencies and the need for vitamin supplementation is rare. The exceptions to this are a need for vitamin K in the immediate newborn period and vitamin D in breastfed infants with dark skin or inadequate sunlight exposure.

Feeding the premature infant in the 20th century.

This article reviews the historical development of feeding the premature infant in the 20th century. It describes the early work determining the energy requirements of the preterm infant, the evolution of the use of human milk and its fortification for these infants, the development of special formulas for very-low-birth-weight infants and the various techniques/methods utilized including total parenteral nutrition.

Fat-soluble vitamin supplements for enterally fed preterm infants.

Fat-soluble vitamin requirements for the enterally fed premature infant are an important concern, both before and after discharge from the neonatal intensive care unit. Because preterm infants fed unsupplemented human milk receive deficient quantities of these vitamins (A, D, E, and K), supplements are very important for this population. Vitamin intakes with special formulas for low birth weight infants and human milk fortifiers are also reviewed.

Are breast-fed infants vitamin K deficient?

Hemorrhagic disease of the newborn is a disease of breast-fed infants. We have followed 119 exclusively breast-fed infants for up to 6 months of age, who received 1 mg of vitamin K, intramuscularly at birth. As vitamin K is undetectable in cord blood, the only other source in breast-fed infants is human milk. We found persistently low vitamin K1 plasma concentrations in these infants by 4 weeks, and vitamin K concentrations at 2, 4, 6, 8, 12, and 26 weeks averaged 1.18+/-0.99, 0.50+/-0.70, 0.16 +/-0.07, 0.20+/-0.20, 0.25+/-0.34, and 0.24+/-0.23 ng/mL, respectively (lower limit of adult normal = 0.5ng/mL). Vitamin K, in breast milk at 2, 6, 12, and 26 weeks was also very low, averaging 1.17+/-0.70, 0.95+/-0.50, 1.15+/-0.62, and 0.87+/-0.50 mg/mL, respectively. This may be secondary to low maternal vitamin K1 intakes or inability of vitamin K1 to penetrate human milk. We had previously reported a relatively high mean vitamin K intake of 316+/-548 microg in 20 lactating women during the first 6 months of lactation (mean of 60, 3-day dietary recalls) which greatly exceeded the recommended daily allowance of 1 microg/kg/day. The vitamin K content of foods was recently revised downward utilizing newer analytical methods (Booth et al. 1995). Recalculating maternal vitamin K intakes in this original cohort resulted in a dramatic decrease in intake to 74+/-57 microg/day, an amount closely approximating 1 microg/kg/day. We have completed 69 new dietary recalls in 23 lactating women and, combining these data with the previous study, determined a maternal vitamin K1 mean intake of 65+/-48 microg/day (0.8-1.3 microg/kg/day). Other than plasma vitamin K1 concentrations, PIVKA (undercarboxylated prothrombin produced in the absence of vitamin K) is a marker of vitamin K deficiency. We measured PIVKA in 156 cord bloods of full-term infants. Seventy-five (48%) had a significantly elevated PIVKA (> or =0.1 absorption units per milliliter). Seventy-seven of these infants who were exclusively breast-fed subsequently had no detectable PIVKA at 4 weeks, but by 8 weeks, 3 were again positive for PIVKA (prothrombin times were normal). Breast-fed infants may benefit from increased maternal vitamin K intakes (>1 microg/kg/day) during pregnancy and lactation. A supplement of 5 mg of vitamin K to lactating mothers will increase the concentration in human milk to 80.0+/-37.7 ng/mL and significantly increase infant plasma vitamin K (Greer et al. 1997).

Urea production is increased in neonatal piglets infused with alanine at 25, 50, and 75% of resting energy needs .

To study the ability of neonatal piglets to metabolize a nitrogen load and excrete it as urea, 12 newborn piglets, 6 small (0.99 +/- 0. 16 kg; expt. 1) and 6 large (1.86 +/- 0.16 kg; expt. 2), were infused intravenously with alanine (n = 8; 4 large, 4 small; treatment) or glucose (n = 4; 2 large, 2 small; control) at equal ATP equivalents, supplying 25-75% of the resting energy requirements of the piglet over 18 h. To adjust for differences in the baseline urinary urea nitrogen excretion, blood urea nitrogen (BUN) and estimated urea production between groups, the absolute changes from baseline to maximum value for piglets infused with alanine, and from baseline to the 24-h value for piglets infused with glucose were evaluated statistically. There were no differences (0.1 < P < 0.3) in the absolute changes from baseline to maximum values of urinary urea nitrogen, BUN or estimated urea production between small [18.6 +/- 3.8 mg N/(h. kg(0.75)); 19.1 +/- 2.2 mmol N/L; 2.7 +/- 1.2 mmol N/(h. kg(0.75)), respectively] and large [23.6 +/- 7.6 mg N/(h. kg(0. 75)); 21.6 +/- 3.3 mmol N/L; 3.7 +/- 1.5 mmol N/(h. kg(0.75)), respectively] piglets infused with alanine. Differences in the changes from baseline were detected between alanine and glucose (P = 0.001) infusions. Small piglets required more time (P < 0.005) for BUN to maximize after initiation of the alanine infusion, suggesting that small piglets require more time to process a nitrogen load. Infusion of alanine resulted in at least a threefold increase from baseline in the rate of calculated urea production, suggesting that neonatal piglets, small or large, have reserve capacity to metabolize nitrogen and excrete it as urea.

Comparison of total body urea production potential with total body carbamoyl phosphate synthetase (CPS-1) activity in newborn piglets infused with alanine at 50% of resting energy expenditure for 36 hours.

The calculated rate of urea production [U(p); mmol urea/(h. kg(0. 75))], based on urinary urea-N (UUN) excretion and changes in total body urea-N, was compared with the calculated total body V(max) of carbamoyl phosphate synthetase (CPS-1) of 24 neonatal piglets from four treatments as follows: 6 h baseline control (n = 8), 18 h of alanine intravenously (IV) at 50% of resting energy expenditure (REE; n = 4), 36 h of alanine IV at 50% of REE (n = 6), or 36 h of glucose IV at 50% of REE (n = 6). The following significant increases from baseline were seen in piglets infused with alanine for 36 h: 1) UUN excretion [10.6 +/- 5.9 mg N/(h. kg(0.75)) to 53.2 +/- 11.1]; 2) BUN concentrations (9.1 +/- 3.0 mmol urea N/L to 51.2 +/- 7.0); 3) calculated urea production [0.34 +/- 0.21 mmol urea/(h. kg(0.75)) to 2.39 +/- 0.53]; and 4) CPS-1 V(max) [2.0 +/- 0.81 mmol citrulline/(h. kg (0.75)) to 4.4 +/- 1.5], (P < 0.05). With the exception of CPS-1 activity, significant decreases from baseline were seen in these values in piglets infused with glucose for 36 h (P < 0.05). Comparison of calculated urea production with calculated total body CPS-1 V(max) at baseline, 18 or 36 h after the start of infusion of alanine or glucose revealed a positive relationship (slope = 0.263; P < 0.002). At all enzyme activities, infusion of alanine resulted in a significant increase in the rate of urea production compared with controls (P < 0.001). Total body CPS-1 activity varied from 1.8 to 5.8 times that of urea production, suggesting that CPS-1 did not limit urea production.

Vitamin metabolism and requirements in the micropremie.

Vitamin metabolism and requirements are reviewed for the micropremie (1000 Pounds g birthweight), for parenteral and enteral feedings. Recommendations are presented in table format. Human milk fortifiers and special formulas for the preterm infant are reviewed. For parenteral nutrition, only MVI Pediatric is currently available in the United States. Two millimeters per kilogram is recommended for the micropremie as the most satisfactory method of providing supplemental vitamins in total parenteral nutrition solutions.

Vitamin K status of lactating mothers and their infants.

Vitamin K deficiency remains a world-wide problem in the newborn. Vitamin K traverses the placenta from mother to infant very poorly and is present only in very low concentrations in human milk. Thus, it is not surprising that the newborn infant has undetectable vitamin K serum levels with abnormal amounts of the coagulation proteins and undercarboxylated prothrombin. Hemorrhagic disease of the newborn, secondary to vitamin K deficiency, remains largely a disease of breastfed infants. Lactating mothers easily achieve the recommended dietary allowance for vitamin K (1 microg kg(-1) d(-1)) and the breast milk concentration is readily increased by increasing maternal vitamin K intake. Breastfed infants do not receive the recommended vitamin K intake via human milk. To prevent vitamin K deficiency in the newborn, intramuscular or oral vitamin K prophylaxis is necessary.

A new mixed micellar preparation for oral vitamin K prophylaxis: randomised controlled comparison with an intramuscular formulation in breast fed infants.

OBJECTIVE: To compare a new oral preparation of vitamin K1 (Konakion MM) containing lecithin and glycocholic acid with a standard intramuscular (IM) preparation during the first 8 weeks of life in exclusively breast fed infants. METHODS: Infants were randomised 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 randomised 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 K1 values (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 (> or = 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.

Improving the vitamin K status of breastfeeding infants with maternal vitamin K supplements.

OBJECTIVE: To increase the phylloquinone (vitamin K1) concentration of human milk with maternal oral phylloquinone supplements such that both the phylloquinone intake of breastfed infants and their serum concentrations of phylloquinone would approach those of formula-fed infants who are known to be at much less risk for hemorrhagic disease of the newborn. DESIGN: Two stages: stage I, longitudinal, randomized study of 6 weeks' duration; and stage II, longitudinal, randomized, double-blind, placebo-controlled study of 12 weeks' duration. SETTING: Patients from a private pediatric practice in Madison, WI. PATIENTS: Stage I: sequential sampling of 20 lactating mothers to determine the level of maternal supplementation needed in stage II. Ten mothers received 2.5 mg/d oral phylloquinone, and 10 mothers received 5.0 mg/d oral phylloquinone. Stage II: sequential sampling of 22 human milk-fed infants and lactating mothers. All infants received 1 mg of phylloquinone at birth. Eleven mothers received a placebo; 11 mothers received 5 mg/d phylloquinone. MEASUREMENTS AND RESULTS: In stage I, both 2.5 and 5.0 mg/d phylloquinone significantly increased the phylloquinone content of human milk at both 2 and 6 weeks. As expected, 5.0 mg had a greater effect (mean +/- SD, 58.96 +/- 25.39 vs 27.12 +/- 12.18 ng/mL at 2 weeks). In stage II, the vitamin K-supplemented group had significantly higher maternal serum phylloquinone concentrations, higher phylloquinone milk concentrations, and higher infant plasma phylloquinone concentrations at 2, 6, and 12 weeks compared with the placebo group. At 12 weeks infant phylloquinone intakes were significantly higher for the vitamin K group than the placebo group (9.37 +/- 4.55 vs 0.15 +/- 0.07 microgram/kg per day). This corresponded to a plasma phylloquinone concentration in the vitamin K group of 2.84 +/- 3.09 vs 0.34 +/- 0.57 ng/mL in the placebo group. At 12 weeks, the prothrombin times did not differ between the groups, but the des-gamma-carboxy-prothrombin (partially carboxylated prothrombin thought to be a measure of vitamin K deficiency) was significantly elevated in the placebo group compared with the vitamin K group (1.48 +/- 1.19 vs 0.42 +/- 0.55 ng/mL). CONCLUSION: In exclusively breastfed infants who receive intramuscular phylloquinone at birth, the vitamin K status as measured by plasma phylloquinone and des-gamma-carboxy-prothrombin concentrations is improved by maternal oral supplements of 5 mg/d phylloquinone through the first 12 weeks of life.

Vitamin K deficiency and hemorrhage in infancy.

Hemorrhage in the infant from vitamin K deficiency is still a concern in pediatrics. Vitamin K given intramuscularly will largely prevent hemorrhagic disease in the newborn, even in infants who are exclusively breast-fed and are thus at the greatest risk for bleeding. The vitamin K content of human milk is very low compared with standard infant formulas. Results with oral vitamin K prophylaxis, currently used in some countries following the association found in a single report between childhood cancer and intramuscular vitamin K, are far more controversial. Any role of vitamin K in the prevention of IVH in premature infants has not been sufficiently demonstrated. Ongoing developments in this field will lead to improved methods of detecting early vitamin K deficiency and perhaps suitable alternatives to intramuscular vitamin K prophylaxis in the newborn.

Neonatal depression after a protamine sulfate injection. A case report.

The intravenous administration of protamine sulfate in adults has been associated with acute hypotension, bradycardia and anaphylactoid reactions. However, no reports of its use in pregnancy have been available before. We describe a case of severe neonatal depression following maternal protamine sulfate injection immediately prior to delivery.

Assessment of vitamin K status of the newborn infant.

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.