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Plasma mineral concentrations in preterm infants fed a nutrient-enriched formula after hospital discharge
Plasma mineral concentrations in preterm infants fed a nutrient-enriched formula after hospital discharge Sujatha Rajaram, PhD, Susan E. Carlson, PhD, Winston W. K. Koo, MBBS, a n d W. E m m e t t Braselton, PhD From the Department of Pediatrics and The Department of Obstetrics and Gynecology, University of Tennessee, Memphis, and the Department of Pharmacology and Toxicology, Michigan State University,East Lansing
Objective: To determine whether prolonged feeding of preterm infant formula to preterm infants can a c c e l e r a t e recovery to normal plasma zinc levels without affecting plasma mineral homeostasis. Design: Part of concurrent prospective feeding trials in a university hospitalbased population. Subjects and intervention: Preterm infants (n = 33; birth weight, 1037 _+ 157 gm) were fed a preterm infant formula with higher concentrations of zinc, copper, calcium, magnesium, and potassium until 2 months past expected term, then a term infant formula. Term infants (n = 38; birth weight, 3318 _+ 401 gm) fed this term infant formula from birth were a reference group for comparison with study infants and with published values. Plasma mineral levels were analyzed by inductively coupled plasma atomic emission spectroscopy. Results: Preterm infants red a preterm infant formula after discharge from the hospital a p p e a r e d to achieve normal plasma zinc concentrations by at least 2 months past term without adverse effects on mineral homeostasis. (J PEDIATR 1995;126:791-6) Currently, nutrient-enriched formula is used routinely in the treatment of hospitalized preterm infants in the United States. Recent reports have also shown that prolonging the feeding of preterm infant formula after discharge of the infant from the hospital can improve nutritional status, l» growth, 4 and bone mineralization. 5 In addition, a zinc sup-
Supported by grants from the National Eye Institute (R01 EY08770), the National Institute of Child Health and Human Development (R01-HD 31329), the National Center for Research Resources (M01 RR00211) and a gift from Ross Products Division, Abbott Laboratories, Columbus, Ohio. Presented in part at the annual meeting of the Federation of American Societies for Biology and published as an abstract in FASEB J 1994;8:A46Ö. Submitted for publication Aug. 24, 1994; accepted Dec. 1, 1994. Reprint requests: Susan E. Carlson, PhD, Newborn Center, Room 201,853 Jefferson Ave., Memphis, TN 38163. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/23/62437
plement provided after patient discharge at levels found in preterm infant formula has been shown to improve Zn status, linear growth velocity, and early motor development. 6 However, data on plasma concentrations of minerals during prolonged feeding of preterm infant formula are minimal. These data may be important because there is presently no assurance that extended feeding of the nutrient-enriched ICP/AES PCA SRM
Inductively coupled plasma atomic emission spectroscopy Postconceptional age Standard reference material
preterm infant formulas does not result in supraphysiologic concentrations of plasma minerals. The goal of this study was to compare Zn, calcium, copper, magnesium, potassium, and iron concentrations of preterm infants red a preterm infant formula until 2 months after expected term delivery. Data from a group of term infants were obtained as a basis for comparison with study infants and as a reference
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T a b l e I. Neonatal and perinatal characteristics of term and preterm infants studied M e a n _+ SD ( r a n g e )
Variable
Birth weight (gm) Gestational age
(wk) Black/white rati0 M/F ratio Apgar (5 min) Maternal age (yr) Maternal height (cm) Gravidity
Term (n = 38)
Preterm (n = 33)
3318 _+ 401 (2600-4190 40.0 _+ 1.0 (38-42) 35:3
1037 + 157 (747-1275) 27.8 _+ 1.4 (24-30) 28:5
18:20 9.0 _+ 0.2 (8-10) 22.0 + 4.0 (17-33) 162.5 _+ 6.3 (150-180) 2.8 +_ 1.2 (1-5)
17:16 7.2 + 1.2 (4-10) 22.0 _+ 5.0 (16-33) 164.1 + 5.9 (152-178) 2.5 _+ 1.2 (14)
group for term infants studied with methods other than inductively coupled plasma atomic emission spectroscopy, the multielement assay used here. METHODS Preterm and term infants were the subjects of separate randomized trials that ran eoncurrently. Each trial was designed primarily to determine whether infant development could be improved by the addition of long-chain n-3 or n-6 fatty acids to formula. Because preterm infants fed term infant formula after discharge had a high incidence of biochemical vitamin A deficiency,2 to avoid the possibility of marginal nutritional status confounding developmental outcomes, both control and experimental preterm groups were red a nutrient-enriched preterm infant formula until 2 months of age (this and all subsequent ages indicate age after expected term). Instead of including the type of formula fed at discharge as part of the randomization, which would have increased the time necessary for enrollment from 3 to 6 years, the decision was made to obtain informa, tion on mineral status, which could be helpful in subsequent randomized trials. The mineral content of the control (Similac Special Care and Similac With Iron, Ross Products Dir., Abbott Laboratories, Columbus, Ohio) and experimental formulas based on these products was identical. Parental consent was obtained before enrollment, according to a protocol approved by the institutional review board of the University of Tennessee, Memphis. If suffieient blood was available for mineral analysis at a planned blood draw (250/A), a separate sample of blood was prepared for mineral analyses (see Blood Collection). Only preterm infants for whom blood
was available from at least three of six planned blood draws and term infants for whom blood was available from at least two of four planned blood draws were included in the analyses. The preterm and term infants constituted subsets of 33 of 59, and 38 of 59 infants, resPectively; their neonatal and perinatal characteristics are shown in Table I. Preterm infants received a parenteral solution containing Zn (3.2 mg/L) and Cu (0.16 mg/L) from approximately 48 hours of age. The volume of parenteral solution was increased to 125 ml/kg per day for 96 hours. Preterm formula was started at approximately 72 hours of age and the volume increased gradually to 150 ml/kg per day, which provided 120 kcal/kg per day (Table II). On average, infants had a postnatal age of 3~ß weeks when they achieved a formula intake of 150 ml/kg per day. Parenteral feedings were decreased gradually and stopped when enteral intakes of preterm formula reached approximately 80 kcal/kg per day. Infants were discharged from the hospital when they weighed approximately 1800 gm but continued receiving preterm formula until 2 months past expected term. They returned for follow-up at 0, 2, 4, 6, 9, and 12 months after term. From 2 to 12 months they were provided a standard formula (Similac With Iron Ross Products Dir., Abbott Laboratories; 5.1 mg/L Zn or 0.75 mg Zn per 100 kcal). Term infants were fed a formula with the same vitamin and mineral composition as Similac With Iron formula from birth through 12 months of age. All formulas were provided at no cost and as needed to parents, and the parents of study infants were encouraged to provide free access to formula as an exelusive feeding to infants to 4 months past term. In addition, parents received money for transportation. Parents were interviewed by a nutritionist at each follow-up visit and asked to describe their child's usual intake of formula. If the diet history was determined to be unreliable, the data were not included. From 4 months past term, both term and preterm infants consumed a mixed diet, which included both formula and variable amounts of other foods. Only reports of recent formula intake obtained at each visit were used to obtain an estimate of mineral intake from formula. Mean reported formula intakes up to age 1 month were 0.20 _+ 0.08 L/kgper dayand0.21 + 0.03 L/kgper dayin term and preterm infants, respectively. Reported formula intake was unchanged through 4 months in term infants and then declined progressively, reaching 0.10 L/kg per day by 12 months. The formula intake of preterm infants declined progressively throughout infancy, reaching 0.08 L/kg per day by 12 months. Blood collection. Heparinized blood samples were colleeted in trace element-free vials (Sarstedt, Newton, N.C.). Samples from preterm infants were collected at term (39 _+ 1 week posteonceptional age) and at 2 (48 _+ 1 weeks PCA), 4 (57 _ 1 weeks PCA), 6 (69 _+ 1 weeks PCA), 9
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(79 _+ 1 weeks PCA), and 12 months (92 _+ 1 weeks PCA). Blood samples from term infants were obtained at 2, 4, 6, and 12 months. Samples were collected between 10 AM and 2 PM, and all infants were well and eating at 3- to 4-hour intervals on the day of sampling; the samples were not postprandial. After immediate separation from blood cells, plasma was stored in sterile polypropylene microtubes (Sarstedt) at - 7 0 ° C until the mineral analyses were performed. Instrumentation and analytic methods. An I C P / A E S , a polyscan 6 l E simultaneous/sequential instrument (Thermo Jarrell Ash Corp., Franklin, Mass.) interlaced to a U-5000 Ultrasonic Nebulizer (Cetac Technologies Inc., Omaha, Neb.), was used for plasma mineral analyses. The validity and sensitivity of the I C P / A E S technique for measuring mineral concentrations in plasma and other biologic fluids have been documented. 79 The small sample necessitated addition of the ultrasonic nebulization teehnique for additional sensitivity. The analysis involved the overnight digestion (95 ° C) of 0.1 ml of plasma with 0.5 ml of Bakeranalyzed Ultrex II nitric acid (Baxter Diagnostics, Inc., McGaw Park, Ill.) in tetrafluoroethylene (Teflon) eontainers (Savillex Corp., Minnetonka, Minn.). After digestion the samples were removed from the oven, cooled to room temperature, and brought to a final volume of 10 ml by gravimetric addition of grade I water (Millipore Corp., Bedford, Mass.) to a predetermined net weight of 10.224 gin. Mineral standards (Johnson-Matthey/Aesar, Ward Hill, Mass.) were made up in 5% nitric acid containing 30 ppm Na to matrix match with the plasma samples. The aeeuracy of the assay was verified by comparing the readings obtained from the standards with National Institute of Standards and Technology (NIST) multielement mix A-1 standard reference material 317 la and multielement mix B SRM 3172, diluted to 1 ppm with 5% nitric acid with 30 ppm Na. Quality eontrol was achieved by determining the concentration of Zn in control bovine serum and/or human serum prepared in the same manner as the samples and cõmparing the values with that of NIST bovine serum (SRM 1598) and/or human serum 909a (NIST, Gaithersburg, Md.). The I C P / A E S value for Zn in 0.1 ml (n = 40) of the eontrol bovine serum (mean _+ SD) is 0.92 _+ 0.14 ppm, and the established mean in bovine serum is 0.92 ppm (range, 0.85 to 0.98 ppm). Our I C P / A E S values for all minerals studied in the certified serum were within 2% to 3% of the established mean and were in the accepted range. Statistical analysis. The General Linear Model procedure of statistical applieation system (SAS) version 6.0 (SAS Institute, Cary, N.C.) was employed for all statistics. After a preliminary analysis, whieh showed that the inelusion of long-chain n-3 or n-6 fatty acids did not influence any plasma mineral, this variable was not considered further. A repeated-measures analysis of variance, corrected for sub-
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Table II. Selected mineral composition of study formulas Nutrient*
Term formula
Preterm formula
K (mg/L) Ca (mg/L) Mg (mg/L) Zn (mg/L) Cu (/~g/L) Fe (mg/L)
710 493 40.6 5.1 608 12.2
1047 1462 97.4 12.2 2030 14.62
*From Ross LaboratoriesProduct Handbook,Ross Products Div., Abbott Laboratories, Colurnbus, Ollio, June 1992. The term infant formula contained676 kcai/L, and the preterminfantformulacontained812 kcal/L. ject effects and missing data, was performed for each mineral to determine the effects of gestational age at birth (term or preterm) and time (study age) on plasma concentration. Within each analysis were 276 individual analyses. The Fisher least significant difference obtained from these analyses was used for comparisons to obtain within-group (study age) and between-group (gestational age at birth) differences. A difference with p <0.05 was considered statistically significant. RESULTS Longitudinal changes in plasma concentrations of K, Ca Mg, Cu, Zn, and Fe are shown in Table III. In both term and preterm infants plasma K generally decreased with increasing age (p <0.0001). The plasma K concentration obtained in preterm infants differed from that of term infants (p <0.009), but this appeared to be due completely to a lower 12-month plasma K concentration in term compared with preterm infants. Mean plasma Ca and Mg concentrations remained constant throughout the study period, and the concentrations were similar in term and preterm infants. The mean plasma Zn concentration in the preterm group at term was significantly lower than at every subsequent age (Table III). However, even at term, most preterm infants (92%) had a plasma Zn concentration greater than 65 ~g/ dl. In term infants the mean plasma Zn concentration increased significantly between 6 and 12 months (p <0.001). Compared with term infants, preterm infants had a significantly higher plasma Zn level at 4 months (p <0.02) and a lower plasma Zn level at 12 mo (p <0.05) of age. There were wide ranges in plasma Cu and Fe concentrations for both term and preterm groups at all ages (Table III). Plasma Cu concentrations also increased significantly with increasing age in both term (p <0.03) and preterm (p <0.0001) infants. Plasma Fe concentration decreased in time (p <0.05) and was higher in preterm compared with term infants (p <0.004). DISCUSSlON Infant formulas specially designed for the nutrient needs of premature infants contain Zn concentrations of 10 to
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TaDle III.Plasma concentrations of K, Ca, Mg, Zn, Cu, and Fe in term and preterm infants during the first year of life K (mmol/L) Age* (mo)
Term
0 2 4 6 9 12
NA 4.8 _+ 0.5 ~ 4.4 _+ 0.5 b 4.3 _+ 0.5 b NA 4.2 _+ 0.6 b
Repeated measures ANOVA Gestational age Study age
Co (mg/dl)
Preterm 5.0 4.8 4.6 4.4 4.4 4.6
-+ 0.6 a _+ 0.6 a'b _+ 0.6 b,c _+ 0.6 c,d _+ 0.7 c'd + 0.7 b'd'~"
0.009 0.0001
Term
M g (mg/dl)
Preterm
NA 9.7 _+ 0.8 9.7 _+ 0.7 9.4 _+ 0.8 NA 9.8 -+ 0.7
9.4 9.9 9.7 9.9 9.8 9.6 NS NS
_+ 1.0 _+ 0.9 _+ 0.9 +_ 1.0 -+ 0.9 -+ 0.9
Term
Preterm
NA 2.0 _+ 0.3 2.0 _+ 0.2 2.0 _+ 0.3 NA 1.9 _+ 0.2
2.1 2.0 2.0 2.0 2.1 2.0
+ 0.3 _+ 0.3 _+ 0.3 + 0.3 + 0.3 _+ 0.3
NS NS
Concentration valuesare least-squares means _+SD from repeated-measuresanalysis of variance. Study ages with different letters as superscripts are significantly different from each other (p <0.05). Conversionfactors for SI units: Ca, mg/dl × 0.25 = mmol/L; Cu,/ig/dl x 0.16 =/~mol/L; Fe, #g/dl X 0.18 = p~mol/L;Mg, mg/dl × 0.41 = ~mol/L; Zn, ug/ dl x 0.15 = ~mol/L. NA, Not available;NS, not significant. *Adjusted for expected term. tPreterm infants differ from term infants of the same age (p <0.05). 12.2 m g / L and are routinely used for in-hospital feeding of preterm infants in the United Stares. However, preterm formulä given only during the hospital stay, with the feeding of standard formula after hospital discharge, 1°14 is not adequate to prevent a decline in plasma Zn levels. 1416 Our data demonstrate that preterm infants fed preterm formula for 2 to 3 months after discharge from the hospital achieve a plasma Zn concentration equivalent to that of term infants on or before an adjusted age of 2 months. The Subcommittee on Recommended Daily Allowances 17 has proposed a Zn intake of 5 m g / d a y for formula-fed term infants, on the basis of the Zn intake of normal breast-fed infants; this value takes into account the lower bioavailability of Zn from formulas. Assuming an absorption of 20%, 18 this would allow for Zn retention of 1 m g / day, and would meet the estimated Zn requirement of healthy term infants in the early postnatal period of 0.8 mg/däy. In our term reference group the mean Zn intake exceeded 5 mg/day, and the mean plasma Zn concentration at each study age was similar to normal adult values. 19 In contrast, preterm infants who presumably retained Zn at approximately 1 m g / d a y for 3 weeks had declines in plasma Zn concentration. 16 The preterm infants in our study had Zn intakes of 9 m g / d a y from term to 2 months. If their Zn absorption was similar to that of formula-fed term infants, they should have bad Zn retention of 1.5 to 2 m g / d a y during this interval. Judging from the fact that they rapidly achieved plasma Zn concentrations similar to those of term infants, this intake appears to have been reasonable. Marginal Zn status has been shown to result in slower growth20, 21 and poorer immune function, 22, 23 and to alter behavior in rats 24 and nonhuman primates. 25 In the only randomized trial to study the effects of supplementing the
diet of preterm infants with Zn after discharge from the hospital, Friel et al. 6 observed higher plasma Zn coneentration, linear growth velocity, and scores for motor development. Additional studies are required to determine whether other improvements in behavior (e.g., those influenced by feeding preterm formula compared with term formula 26 and human milk 27) are associated with Zn intake from different types of feedings. Plasma K, Ca, and M g concentrations are normally well regulated and maintained within narrow ranges. 28 Despite intakes of Ca and M g from preterm infant formula two times higher than those from standard formula, the preterm infants studied here had concentrations of plasma Ca and Mg eomparable to those of formula-fed term infants. Higher K intakes of preterm compared with term infants did not influence plasma K coneentration during the first 2 months of infancy, and both term and preterm infants had a normal decline in plasma K concentration in time. Plasma Cu does not rettect hepatic Cu stores immediately after preterm birth, presumably because ceruloplasmin concentration is low. 29 Hence a low plasma Cu concenträtion does not necessarily indieate poor Cu stores. The mean Cu concentration of 61 ~ g / d l in preterm infants at term corrected age was lower than the normal reference range for adults (80 to 120 ~g/dl) but increased to within normal limits by 2 months past term. A similar increase was reported up to 3 months of age by L ' A b b e and Friel 1 in infants, regardless of dietary Cu intake. The progressive increase in plasma Cu throughout infaney in term and preterm infants was virtually identical to that reported by these authors and also did not appear to be influenced by Cu intake. Nevertheless, the group fed Cu intakes two times higher until 3 months past term had higher erythrocyte Cu,
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Table III--cont'd
Term
Preterm
NA 93.3 + 18.6a 92.0 ± 18.1a 97.3 -+ 18.4a NA 112.9 -+ 18.4b
Fe (ug/dl)
Cu (~,g/dl)
Zn (~.g/dl)
80.1 101.4 106.6 103.2 106.7 100.9
+_ 19.0a + 18.5b ± 19.1b't _+ 18.6b ± 19.1b _+ 18.7b,?
Term
Preterm
NA 84.2 _+ 39.4 a 105.7 ± 38.5 b 112.6 ± 39.1 b NA 144.0 _+ 38.5 c
NS 0.0002
Z n - s u p e r o x i d e dismutase levels, suggesting there was an advantage to prolonged feeding of higher Cu intakes. 1 Because both term and preterm infants received formulas with 1.8 mg Fe per 100 kcal, we cannot explain why plasma Fe concentration during infancy was somewhat higher in p r e t e r m compared with term infants. This may have been related to early erythrocyte transfusions received by preterm infants. There was also a small but significant decrease in plasma Fe in time in both term and preterm infants; this decrease fits with parental reports that infants gradually replaced energy from Fe-fortified formula with that from foods lower in Fe concentration. Despite these significant differences, however, the means in plasma for both term and preterm infants at all ages were well within the normal adult range of 35 to 140 #g/dl. 3° W e conclude that prolonged feeding of nutrient-enriched formula to preterm infants can accelerate achievement of normal plasma Z n values in preterm infants without adverse effects on other plasma mineral levels. The technical assistance of Kirk Stuart is gratefully acknowledged. We appreciate the assistance of Susan Werkman and Amy Ford in conducting this study. REFERENCES
1. L'Abbe MR, Fr±el JK. Copper status of very low birth weight infants during the first 12 months of infancy. Pediatr Res 1992;32:183-8. 2. Peeples JM, Carlson SE, Werkman SH, Cooke RJ. Vitamin A status of preterm infants during infancy. Am J Clin Nutr 1991;53:1455-9. 3. Carlson SE, Peeples JM, Werkman SH, Koo WWK. Plasma retinol and retinol binding protein concentrations in very preterm infants fed preterm formula in early infancy. Eur J Clin Nutr (in press). 4. Lucas A, Bishop NJ, King F J, Cole TJ. Randomised trial of nutrition for preterm infants after discharge. Arch Dis Child 1992;67:324-7. 5. Bishop NJ, King F J, Lucas A. Increased borte mineral content of preterm infants fed with a nutrient enriched formula after discharge from hospital. Arch Dis Child 1993;68:573-8.
61.5 85.8 111.8 121.1 139.8 147.3 NS 0.001
_+ 41 a _+ 40b ± 42c ± 41 c'd ± 42d + 42d
Term
Preterm
NA 88.3 -+ 31.4 72.0 ± 30.2 70.4 + 29.3 NA 81.3 _+ 30.5
92.7 108.4 106.2 84.1 85.4 88.7
± 55 _+ 55 ± 57t ± 56 ± 55 ± 58
0.004 0.05
6. Fr±el JK, Andrews WL, Matthew JD, et al. Zinc supplementat±on in very low birth weight infants. J Pediatr Gastroenterol Nutr 1993;17:97-104. 7. Stowe HD, Braselton WE, Slanker M, Kaneene JB. Multielement assays of canine serum, liver, and kidney by inductively coupled argon plasma emission spectroscopy. Am J Ver Res 1986;47:822-7. 8. Fassel VA. Quantitative elemental analyses by plasma emission spectroscopy. Science 1978;202:183-91. 9. Nixon DE, Moyer TP, Johnson P, et al. Routine measurement of calcium, magnesium, copper, zinc and iron in urine and serum by inductively coupled plasma emission spectroscopy. Clin Chem 1986;32:1660-5. 10. Gibson RS, Dewolfe MS. Changes in serum zinc concentrations of some Canadian full term and low birthweight infants from birth to six months. Acta Paediatr Scand 1981;70:497500. 1 I. Altigani M, Murphy JF, Gray OP. Plasma zinc concentration and catch up growth in preterm infants. Acta Paediatr Scand S u p p l 1989;357:20-33. 12. Fr±el JK, Gibson RS, Peliowski AD, Watts J. Serum zinc, copper and selenium concentrations in preterm infants receiving enteral nutrition or parenteral nutrition supplemented with zinc and copper. J PEDIATR 1984;104:763-8. 13. McMaster D, Lappin TRJ, Halliday HL, Patterson CC. Serum copper and zinc levels in the preterm infant: a longitudinal study of the first year of life. Biol Neonate 1983;44:10813. 14. Tyrala EE, Manser JI, Brodsky NL, et al. Serum zinc concentrations in growing premature infants. Acta Paediatr Scand 1983;72:695-8. 15. Koo WW, Succop P, Hambidge KM. Serum alkaline phosphatase and serum zinc concentrations in preterm infants with rickets and fractures. Am J Dis Chitd 1989;143:1342-5. 16. Tyrala EE. Zinc and copper balances in preterm infants. Pediatrics 1986;77:513-7. 17. Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council. Recommended dietary allowances. Washington, DC: National Academy Press, 1989:205-11. 18. Hambidge KM, Krebs NF. Upper limits of zinc, copper and manganese in infant formulas. J Nutr 1989;119:1861-4. 19. Pilch SM, Senti FR, eds. Assessment of zinc nutritional status of the U.S. population based on data collected in the Second National Health and Nutrition Examination Survey, 1979.
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20. 21.
22. 23.
24.
25.
Demarini et al.
1980. Bethesda, Md: Life Sciences Research Office, Federation of American Societies for Experimental Biology, 1984. Walravens PA, Hambidge KM. Growth of infants fed a zinc supplemented formula. Am J Clin Nutr 1976;29:1114-21. Walravens PA, Krebs NF, Hambidge KM. Linear growth of low ineome preschool children receiving a zinc supplement. Am J Clin Nutr 1983;38:195-201. Chandra KP, Au B. Single nutrient deficiency and cell-mediated immune responses. I. Zinc. Am J Clin Nutr 1980;33:736-8. Schlesinger L, Arevalo M, Arrendondo S, et al. Effect of a zinc-fortified formula on immunocompetence and growth of malnourished infants. Am J Clin Nutr 1992;56:491-8. Halas ES, Heinrich MD, Sandstead HH. Long-term memory deficits in adult rats due to postnatal malnutrition. Physiol Behav 1979;22:991-7. Golub MS, Gershwin ME, Hurley LS, Hendrickx AG, Saito
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26.
27.
28. 29.
30.
WY. Studies of marginal zinc deprivation in rhesus monkeys: infant behavior. Am J Clin Nutr 1985;42:1229-39. Lucas A, Morley R, Cole T J, et al. Early diet in preterm babies and developmental status at 18 months. Lancet 1990;335:1477-81. Lucas A, Morley R, Cole T J, et al. Early diet in preterm babies and developmental status in infancy. Arch Dis Child 1989;64:1570-8. Gibson RS. Principles of nutritional assessment. New York: Oxford University Press, 1990:487-510. Hillman LS. Serial serum copper concentrations in premature and SGA infants during the first 3 months of life. J PEDIATR 1981;98:305-8. Cook JD, Bothwell TH, Covell AM, et al. Reports of the International Nutrition Anemia Consultative Group. Washington, DC: The Nutrition Foundation, 1985.
Clinical and laboratory observations Evidence of increased intrauterine bone resorption in term infants of mothers with insulin-dependent diabetes Sergio Demarini, MD, Bonny L. Specker, PhD, Rosa I. Sierra, MS, M e n a c h e m Miodovnik, Mb, and Reginald C. Tsang, MBB$ From the Perinatal Research institute, Division of Neonatology, Departments of Pediatrics and of Obstetrics and Gynecology, University of Cincinnati Medical Center, Children's Hospital Medical Center, Cincinnati, Ohio
Infants of diabetic mothers (IDMs) h a v e lower b o n e mineral content than control subjects at birth. We measured cord blood p r o p e p t i d e of type I p r o c o l l a g e n (PICP), a marker of b o n e formation, a n d t e l o p e p t i d e of type I c o l l a g e n (ICTP), a marker of b o n e resorption, in 25 term IDMs and 20 term control subjects. Concentrations of ICTP were higher in IDMs than in control subjects; there was no difference in PICP concentrations. We c o n c l u d e that osteoclastic activity a p p e a r s to be higher in IDMs than in control subjects in utero. (J PEDIATR1995;126:7968) Supported in part by the Diabetes in Pregnancy Program Project (HICHD 11725) and by a grant from the J. Miglierina Foundation, Varese, Italy (Dr. Demarini), Submitted for publication Aug. 5, 1994; accepted Nov. 14, 1994.
Reprint requests: Reginald C. Tsang, MBBS, Department of Pediatrics, University of Cincinnati Medical Center, 231 Bethesda Ave., ML 541, Cincinnati, OH 45267-0541. Copyright ® 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/24/62071
Objective: To determine whether prolonged feeding of preterm infant formula to preterm infants can a c c e l e r a t e recovery to normal plasma zinc levels without affecting plasma mineral homeostasis. Design: Part of concurrent prospective feeding trials in a university hospitalbased population. Subjects and intervention: Preterm infants (n = 33; birth weight, 1037 _+ 157 gm) were fed a preterm infant formula with higher concentrations of zinc, copper, calcium, magnesium, and potassium until 2 months past expected term, then a term infant formula. Term infants (n = 38; birth weight, 3318 _+ 401 gm) fed this term infant formula from birth were a reference group for comparison with study infants and with published values. Plasma mineral levels were analyzed by inductively coupled plasma atomic emission spectroscopy. Results: Preterm infants red a preterm infant formula after discharge from the hospital a p p e a r e d to achieve normal plasma zinc concentrations by at least 2 months past term without adverse effects on mineral homeostasis. (J PEDIATR 1995;126:791-6) Currently, nutrient-enriched formula is used routinely in the treatment of hospitalized preterm infants in the United States. Recent reports have also shown that prolonging the feeding of preterm infant formula after discharge of the infant from the hospital can improve nutritional status, l» growth, 4 and bone mineralization. 5 In addition, a zinc sup-
Supported by grants from the National Eye Institute (R01 EY08770), the National Institute of Child Health and Human Development (R01-HD 31329), the National Center for Research Resources (M01 RR00211) and a gift from Ross Products Division, Abbott Laboratories, Columbus, Ohio. Presented in part at the annual meeting of the Federation of American Societies for Biology and published as an abstract in FASEB J 1994;8:A46Ö. Submitted for publication Aug. 24, 1994; accepted Dec. 1, 1994. Reprint requests: Susan E. Carlson, PhD, Newborn Center, Room 201,853 Jefferson Ave., Memphis, TN 38163. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/23/62437
plement provided after patient discharge at levels found in preterm infant formula has been shown to improve Zn status, linear growth velocity, and early motor development. 6 However, data on plasma concentrations of minerals during prolonged feeding of preterm infant formula are minimal. These data may be important because there is presently no assurance that extended feeding of the nutrient-enriched ICP/AES PCA SRM
Inductively coupled plasma atomic emission spectroscopy Postconceptional age Standard reference material
preterm infant formulas does not result in supraphysiologic concentrations of plasma minerals. The goal of this study was to compare Zn, calcium, copper, magnesium, potassium, and iron concentrations of preterm infants red a preterm infant formula until 2 months after expected term delivery. Data from a group of term infants were obtained as a basis for comparison with study infants and as a reference
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T a b l e I. Neonatal and perinatal characteristics of term and preterm infants studied M e a n _+ SD ( r a n g e )
Variable
Birth weight (gm) Gestational age
(wk) Black/white rati0 M/F ratio Apgar (5 min) Maternal age (yr) Maternal height (cm) Gravidity
Term (n = 38)
Preterm (n = 33)
3318 _+ 401 (2600-4190 40.0 _+ 1.0 (38-42) 35:3
1037 + 157 (747-1275) 27.8 _+ 1.4 (24-30) 28:5
18:20 9.0 _+ 0.2 (8-10) 22.0 + 4.0 (17-33) 162.5 _+ 6.3 (150-180) 2.8 +_ 1.2 (1-5)
17:16 7.2 + 1.2 (4-10) 22.0 _+ 5.0 (16-33) 164.1 + 5.9 (152-178) 2.5 _+ 1.2 (14)
group for term infants studied with methods other than inductively coupled plasma atomic emission spectroscopy, the multielement assay used here. METHODS Preterm and term infants were the subjects of separate randomized trials that ran eoncurrently. Each trial was designed primarily to determine whether infant development could be improved by the addition of long-chain n-3 or n-6 fatty acids to formula. Because preterm infants fed term infant formula after discharge had a high incidence of biochemical vitamin A deficiency,2 to avoid the possibility of marginal nutritional status confounding developmental outcomes, both control and experimental preterm groups were red a nutrient-enriched preterm infant formula until 2 months of age (this and all subsequent ages indicate age after expected term). Instead of including the type of formula fed at discharge as part of the randomization, which would have increased the time necessary for enrollment from 3 to 6 years, the decision was made to obtain informa, tion on mineral status, which could be helpful in subsequent randomized trials. The mineral content of the control (Similac Special Care and Similac With Iron, Ross Products Dir., Abbott Laboratories, Columbus, Ohio) and experimental formulas based on these products was identical. Parental consent was obtained before enrollment, according to a protocol approved by the institutional review board of the University of Tennessee, Memphis. If suffieient blood was available for mineral analysis at a planned blood draw (250/A), a separate sample of blood was prepared for mineral analyses (see Blood Collection). Only preterm infants for whom blood
was available from at least three of six planned blood draws and term infants for whom blood was available from at least two of four planned blood draws were included in the analyses. The preterm and term infants constituted subsets of 33 of 59, and 38 of 59 infants, resPectively; their neonatal and perinatal characteristics are shown in Table I. Preterm infants received a parenteral solution containing Zn (3.2 mg/L) and Cu (0.16 mg/L) from approximately 48 hours of age. The volume of parenteral solution was increased to 125 ml/kg per day for 96 hours. Preterm formula was started at approximately 72 hours of age and the volume increased gradually to 150 ml/kg per day, which provided 120 kcal/kg per day (Table II). On average, infants had a postnatal age of 3~ß weeks when they achieved a formula intake of 150 ml/kg per day. Parenteral feedings were decreased gradually and stopped when enteral intakes of preterm formula reached approximately 80 kcal/kg per day. Infants were discharged from the hospital when they weighed approximately 1800 gm but continued receiving preterm formula until 2 months past expected term. They returned for follow-up at 0, 2, 4, 6, 9, and 12 months after term. From 2 to 12 months they were provided a standard formula (Similac With Iron Ross Products Dir., Abbott Laboratories; 5.1 mg/L Zn or 0.75 mg Zn per 100 kcal). Term infants were fed a formula with the same vitamin and mineral composition as Similac With Iron formula from birth through 12 months of age. All formulas were provided at no cost and as needed to parents, and the parents of study infants were encouraged to provide free access to formula as an exelusive feeding to infants to 4 months past term. In addition, parents received money for transportation. Parents were interviewed by a nutritionist at each follow-up visit and asked to describe their child's usual intake of formula. If the diet history was determined to be unreliable, the data were not included. From 4 months past term, both term and preterm infants consumed a mixed diet, which included both formula and variable amounts of other foods. Only reports of recent formula intake obtained at each visit were used to obtain an estimate of mineral intake from formula. Mean reported formula intakes up to age 1 month were 0.20 _+ 0.08 L/kgper dayand0.21 + 0.03 L/kgper dayin term and preterm infants, respectively. Reported formula intake was unchanged through 4 months in term infants and then declined progressively, reaching 0.10 L/kg per day by 12 months. The formula intake of preterm infants declined progressively throughout infancy, reaching 0.08 L/kg per day by 12 months. Blood collection. Heparinized blood samples were colleeted in trace element-free vials (Sarstedt, Newton, N.C.). Samples from preterm infants were collected at term (39 _+ 1 week posteonceptional age) and at 2 (48 _+ 1 weeks PCA), 4 (57 _ 1 weeks PCA), 6 (69 _+ 1 weeks PCA), 9
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(79 _+ 1 weeks PCA), and 12 months (92 _+ 1 weeks PCA). Blood samples from term infants were obtained at 2, 4, 6, and 12 months. Samples were collected between 10 AM and 2 PM, and all infants were well and eating at 3- to 4-hour intervals on the day of sampling; the samples were not postprandial. After immediate separation from blood cells, plasma was stored in sterile polypropylene microtubes (Sarstedt) at - 7 0 ° C until the mineral analyses were performed. Instrumentation and analytic methods. An I C P / A E S , a polyscan 6 l E simultaneous/sequential instrument (Thermo Jarrell Ash Corp., Franklin, Mass.) interlaced to a U-5000 Ultrasonic Nebulizer (Cetac Technologies Inc., Omaha, Neb.), was used for plasma mineral analyses. The validity and sensitivity of the I C P / A E S technique for measuring mineral concentrations in plasma and other biologic fluids have been documented. 79 The small sample necessitated addition of the ultrasonic nebulization teehnique for additional sensitivity. The analysis involved the overnight digestion (95 ° C) of 0.1 ml of plasma with 0.5 ml of Bakeranalyzed Ultrex II nitric acid (Baxter Diagnostics, Inc., McGaw Park, Ill.) in tetrafluoroethylene (Teflon) eontainers (Savillex Corp., Minnetonka, Minn.). After digestion the samples were removed from the oven, cooled to room temperature, and brought to a final volume of 10 ml by gravimetric addition of grade I water (Millipore Corp., Bedford, Mass.) to a predetermined net weight of 10.224 gin. Mineral standards (Johnson-Matthey/Aesar, Ward Hill, Mass.) were made up in 5% nitric acid containing 30 ppm Na to matrix match with the plasma samples. The aeeuracy of the assay was verified by comparing the readings obtained from the standards with National Institute of Standards and Technology (NIST) multielement mix A-1 standard reference material 317 la and multielement mix B SRM 3172, diluted to 1 ppm with 5% nitric acid with 30 ppm Na. Quality eontrol was achieved by determining the concentration of Zn in control bovine serum and/or human serum prepared in the same manner as the samples and cõmparing the values with that of NIST bovine serum (SRM 1598) and/or human serum 909a (NIST, Gaithersburg, Md.). The I C P / A E S value for Zn in 0.1 ml (n = 40) of the eontrol bovine serum (mean _+ SD) is 0.92 _+ 0.14 ppm, and the established mean in bovine serum is 0.92 ppm (range, 0.85 to 0.98 ppm). Our I C P / A E S values for all minerals studied in the certified serum were within 2% to 3% of the established mean and were in the accepted range. Statistical analysis. The General Linear Model procedure of statistical applieation system (SAS) version 6.0 (SAS Institute, Cary, N.C.) was employed for all statistics. After a preliminary analysis, whieh showed that the inelusion of long-chain n-3 or n-6 fatty acids did not influence any plasma mineral, this variable was not considered further. A repeated-measures analysis of variance, corrected for sub-
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793
Table II. Selected mineral composition of study formulas Nutrient*
Term formula
Preterm formula
K (mg/L) Ca (mg/L) Mg (mg/L) Zn (mg/L) Cu (/~g/L) Fe (mg/L)
710 493 40.6 5.1 608 12.2
1047 1462 97.4 12.2 2030 14.62
*From Ross LaboratoriesProduct Handbook,Ross Products Div., Abbott Laboratories, Colurnbus, Ollio, June 1992. The term infant formula contained676 kcai/L, and the preterminfantformulacontained812 kcal/L. ject effects and missing data, was performed for each mineral to determine the effects of gestational age at birth (term or preterm) and time (study age) on plasma concentration. Within each analysis were 276 individual analyses. The Fisher least significant difference obtained from these analyses was used for comparisons to obtain within-group (study age) and between-group (gestational age at birth) differences. A difference with p <0.05 was considered statistically significant. RESULTS Longitudinal changes in plasma concentrations of K, Ca Mg, Cu, Zn, and Fe are shown in Table III. In both term and preterm infants plasma K generally decreased with increasing age (p <0.0001). The plasma K concentration obtained in preterm infants differed from that of term infants (p <0.009), but this appeared to be due completely to a lower 12-month plasma K concentration in term compared with preterm infants. Mean plasma Ca and Mg concentrations remained constant throughout the study period, and the concentrations were similar in term and preterm infants. The mean plasma Zn concentration in the preterm group at term was significantly lower than at every subsequent age (Table III). However, even at term, most preterm infants (92%) had a plasma Zn concentration greater than 65 ~g/ dl. In term infants the mean plasma Zn concentration increased significantly between 6 and 12 months (p <0.001). Compared with term infants, preterm infants had a significantly higher plasma Zn level at 4 months (p <0.02) and a lower plasma Zn level at 12 mo (p <0.05) of age. There were wide ranges in plasma Cu and Fe concentrations for both term and preterm groups at all ages (Table III). Plasma Cu concentrations also increased significantly with increasing age in both term (p <0.03) and preterm (p <0.0001) infants. Plasma Fe concentration decreased in time (p <0.05) and was higher in preterm compared with term infants (p <0.004). DISCUSSlON Infant formulas specially designed for the nutrient needs of premature infants contain Zn concentrations of 10 to
794
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The JournaI o f Pediatrics May 1995
TaDle III.Plasma concentrations of K, Ca, Mg, Zn, Cu, and Fe in term and preterm infants during the first year of life K (mmol/L) Age* (mo)
Term
0 2 4 6 9 12
NA 4.8 _+ 0.5 ~ 4.4 _+ 0.5 b 4.3 _+ 0.5 b NA 4.2 _+ 0.6 b
Repeated measures ANOVA Gestational age Study age
Co (mg/dl)
Preterm 5.0 4.8 4.6 4.4 4.4 4.6
-+ 0.6 a _+ 0.6 a'b _+ 0.6 b,c _+ 0.6 c,d _+ 0.7 c'd + 0.7 b'd'~"
0.009 0.0001
Term
M g (mg/dl)
Preterm
NA 9.7 _+ 0.8 9.7 _+ 0.7 9.4 _+ 0.8 NA 9.8 -+ 0.7
9.4 9.9 9.7 9.9 9.8 9.6 NS NS
_+ 1.0 _+ 0.9 _+ 0.9 +_ 1.0 -+ 0.9 -+ 0.9
Term
Preterm
NA 2.0 _+ 0.3 2.0 _+ 0.2 2.0 _+ 0.3 NA 1.9 _+ 0.2
2.1 2.0 2.0 2.0 2.1 2.0
+ 0.3 _+ 0.3 _+ 0.3 + 0.3 + 0.3 _+ 0.3
NS NS
Concentration valuesare least-squares means _+SD from repeated-measuresanalysis of variance. Study ages with different letters as superscripts are significantly different from each other (p <0.05). Conversionfactors for SI units: Ca, mg/dl × 0.25 = mmol/L; Cu,/ig/dl x 0.16 =/~mol/L; Fe, #g/dl X 0.18 = p~mol/L;Mg, mg/dl × 0.41 = ~mol/L; Zn, ug/ dl x 0.15 = ~mol/L. NA, Not available;NS, not significant. *Adjusted for expected term. tPreterm infants differ from term infants of the same age (p <0.05). 12.2 m g / L and are routinely used for in-hospital feeding of preterm infants in the United Stares. However, preterm formulä given only during the hospital stay, with the feeding of standard formula after hospital discharge, 1°14 is not adequate to prevent a decline in plasma Zn levels. 1416 Our data demonstrate that preterm infants fed preterm formula for 2 to 3 months after discharge from the hospital achieve a plasma Zn concentration equivalent to that of term infants on or before an adjusted age of 2 months. The Subcommittee on Recommended Daily Allowances 17 has proposed a Zn intake of 5 m g / d a y for formula-fed term infants, on the basis of the Zn intake of normal breast-fed infants; this value takes into account the lower bioavailability of Zn from formulas. Assuming an absorption of 20%, 18 this would allow for Zn retention of 1 m g / day, and would meet the estimated Zn requirement of healthy term infants in the early postnatal period of 0.8 mg/däy. In our term reference group the mean Zn intake exceeded 5 mg/day, and the mean plasma Zn concentration at each study age was similar to normal adult values. 19 In contrast, preterm infants who presumably retained Zn at approximately 1 m g / d a y for 3 weeks had declines in plasma Zn concentration. 16 The preterm infants in our study had Zn intakes of 9 m g / d a y from term to 2 months. If their Zn absorption was similar to that of formula-fed term infants, they should have bad Zn retention of 1.5 to 2 m g / d a y during this interval. Judging from the fact that they rapidly achieved plasma Zn concentrations similar to those of term infants, this intake appears to have been reasonable. Marginal Zn status has been shown to result in slower growth20, 21 and poorer immune function, 22, 23 and to alter behavior in rats 24 and nonhuman primates. 25 In the only randomized trial to study the effects of supplementing the
diet of preterm infants with Zn after discharge from the hospital, Friel et al. 6 observed higher plasma Zn coneentration, linear growth velocity, and scores for motor development. Additional studies are required to determine whether other improvements in behavior (e.g., those influenced by feeding preterm formula compared with term formula 26 and human milk 27) are associated with Zn intake from different types of feedings. Plasma K, Ca, and M g concentrations are normally well regulated and maintained within narrow ranges. 28 Despite intakes of Ca and M g from preterm infant formula two times higher than those from standard formula, the preterm infants studied here had concentrations of plasma Ca and Mg eomparable to those of formula-fed term infants. Higher K intakes of preterm compared with term infants did not influence plasma K coneentration during the first 2 months of infancy, and both term and preterm infants had a normal decline in plasma K concentration in time. Plasma Cu does not rettect hepatic Cu stores immediately after preterm birth, presumably because ceruloplasmin concentration is low. 29 Hence a low plasma Cu concenträtion does not necessarily indieate poor Cu stores. The mean Cu concentration of 61 ~ g / d l in preterm infants at term corrected age was lower than the normal reference range for adults (80 to 120 ~g/dl) but increased to within normal limits by 2 months past term. A similar increase was reported up to 3 months of age by L ' A b b e and Friel 1 in infants, regardless of dietary Cu intake. The progressive increase in plasma Cu throughout infaney in term and preterm infants was virtually identical to that reported by these authors and also did not appear to be influenced by Cu intake. Nevertheless, the group fed Cu intakes two times higher until 3 months past term had higher erythrocyte Cu,
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R a j a r a m et al.
795
Table III--cont'd
Term
Preterm
NA 93.3 + 18.6a 92.0 ± 18.1a 97.3 -+ 18.4a NA 112.9 -+ 18.4b
Fe (ug/dl)
Cu (~,g/dl)
Zn (~.g/dl)
80.1 101.4 106.6 103.2 106.7 100.9
+_ 19.0a + 18.5b ± 19.1b't _+ 18.6b ± 19.1b _+ 18.7b,?
Term
Preterm
NA 84.2 _+ 39.4 a 105.7 ± 38.5 b 112.6 ± 39.1 b NA 144.0 _+ 38.5 c
NS 0.0002
Z n - s u p e r o x i d e dismutase levels, suggesting there was an advantage to prolonged feeding of higher Cu intakes. 1 Because both term and preterm infants received formulas with 1.8 mg Fe per 100 kcal, we cannot explain why plasma Fe concentration during infancy was somewhat higher in p r e t e r m compared with term infants. This may have been related to early erythrocyte transfusions received by preterm infants. There was also a small but significant decrease in plasma Fe in time in both term and preterm infants; this decrease fits with parental reports that infants gradually replaced energy from Fe-fortified formula with that from foods lower in Fe concentration. Despite these significant differences, however, the means in plasma for both term and preterm infants at all ages were well within the normal adult range of 35 to 140 #g/dl. 3° W e conclude that prolonged feeding of nutrient-enriched formula to preterm infants can accelerate achievement of normal plasma Z n values in preterm infants without adverse effects on other plasma mineral levels. The technical assistance of Kirk Stuart is gratefully acknowledged. We appreciate the assistance of Susan Werkman and Amy Ford in conducting this study. REFERENCES
1. L'Abbe MR, Fr±el JK. Copper status of very low birth weight infants during the first 12 months of infancy. Pediatr Res 1992;32:183-8. 2. Peeples JM, Carlson SE, Werkman SH, Cooke RJ. Vitamin A status of preterm infants during infancy. Am J Clin Nutr 1991;53:1455-9. 3. Carlson SE, Peeples JM, Werkman SH, Koo WWK. Plasma retinol and retinol binding protein concentrations in very preterm infants fed preterm formula in early infancy. Eur J Clin Nutr (in press). 4. Lucas A, Bishop NJ, King F J, Cole TJ. Randomised trial of nutrition for preterm infants after discharge. Arch Dis Child 1992;67:324-7. 5. Bishop NJ, King F J, Lucas A. Increased borte mineral content of preterm infants fed with a nutrient enriched formula after discharge from hospital. Arch Dis Child 1993;68:573-8.
61.5 85.8 111.8 121.1 139.8 147.3 NS 0.001
_+ 41 a _+ 40b ± 42c ± 41 c'd ± 42d + 42d
Term
Preterm
NA 88.3 -+ 31.4 72.0 ± 30.2 70.4 + 29.3 NA 81.3 _+ 30.5
92.7 108.4 106.2 84.1 85.4 88.7
± 55 _+ 55 ± 57t ± 56 ± 55 ± 58
0.004 0.05
6. Fr±el JK, Andrews WL, Matthew JD, et al. Zinc supplementat±on in very low birth weight infants. J Pediatr Gastroenterol Nutr 1993;17:97-104. 7. Stowe HD, Braselton WE, Slanker M, Kaneene JB. Multielement assays of canine serum, liver, and kidney by inductively coupled argon plasma emission spectroscopy. Am J Ver Res 1986;47:822-7. 8. Fassel VA. Quantitative elemental analyses by plasma emission spectroscopy. Science 1978;202:183-91. 9. Nixon DE, Moyer TP, Johnson P, et al. Routine measurement of calcium, magnesium, copper, zinc and iron in urine and serum by inductively coupled plasma emission spectroscopy. Clin Chem 1986;32:1660-5. 10. Gibson RS, Dewolfe MS. Changes in serum zinc concentrations of some Canadian full term and low birthweight infants from birth to six months. Acta Paediatr Scand 1981;70:497500. 1 I. Altigani M, Murphy JF, Gray OP. Plasma zinc concentration and catch up growth in preterm infants. Acta Paediatr Scand S u p p l 1989;357:20-33. 12. Fr±el JK, Gibson RS, Peliowski AD, Watts J. Serum zinc, copper and selenium concentrations in preterm infants receiving enteral nutrition or parenteral nutrition supplemented with zinc and copper. J PEDIATR 1984;104:763-8. 13. McMaster D, Lappin TRJ, Halliday HL, Patterson CC. Serum copper and zinc levels in the preterm infant: a longitudinal study of the first year of life. Biol Neonate 1983;44:10813. 14. Tyrala EE, Manser JI, Brodsky NL, et al. Serum zinc concentrations in growing premature infants. Acta Paediatr Scand 1983;72:695-8. 15. Koo WW, Succop P, Hambidge KM. Serum alkaline phosphatase and serum zinc concentrations in preterm infants with rickets and fractures. Am J Dis Chitd 1989;143:1342-5. 16. Tyrala EE. Zinc and copper balances in preterm infants. Pediatrics 1986;77:513-7. 17. Subcommittee on the Tenth Edition of the RDAs, Food and Nutrition Board, Commission on Life Sciences, National Research Council. Recommended dietary allowances. Washington, DC: National Academy Press, 1989:205-11. 18. Hambidge KM, Krebs NF. Upper limits of zinc, copper and manganese in infant formulas. J Nutr 1989;119:1861-4. 19. Pilch SM, Senti FR, eds. Assessment of zinc nutritional status of the U.S. population based on data collected in the Second National Health and Nutrition Examination Survey, 1979.
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1980. Bethesda, Md: Life Sciences Research Office, Federation of American Societies for Experimental Biology, 1984. Walravens PA, Hambidge KM. Growth of infants fed a zinc supplemented formula. Am J Clin Nutr 1976;29:1114-21. Walravens PA, Krebs NF, Hambidge KM. Linear growth of low ineome preschool children receiving a zinc supplement. Am J Clin Nutr 1983;38:195-201. Chandra KP, Au B. Single nutrient deficiency and cell-mediated immune responses. I. Zinc. Am J Clin Nutr 1980;33:736-8. Schlesinger L, Arevalo M, Arrendondo S, et al. Effect of a zinc-fortified formula on immunocompetence and growth of malnourished infants. Am J Clin Nutr 1992;56:491-8. Halas ES, Heinrich MD, Sandstead HH. Long-term memory deficits in adult rats due to postnatal malnutrition. Physiol Behav 1979;22:991-7. Golub MS, Gershwin ME, Hurley LS, Hendrickx AG, Saito
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26.
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28. 29.
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WY. Studies of marginal zinc deprivation in rhesus monkeys: infant behavior. Am J Clin Nutr 1985;42:1229-39. Lucas A, Morley R, Cole T J, et al. Early diet in preterm babies and developmental status at 18 months. Lancet 1990;335:1477-81. Lucas A, Morley R, Cole T J, et al. Early diet in preterm babies and developmental status in infancy. Arch Dis Child 1989;64:1570-8. Gibson RS. Principles of nutritional assessment. New York: Oxford University Press, 1990:487-510. Hillman LS. Serial serum copper concentrations in premature and SGA infants during the first 3 months of life. J PEDIATR 1981;98:305-8. Cook JD, Bothwell TH, Covell AM, et al. Reports of the International Nutrition Anemia Consultative Group. Washington, DC: The Nutrition Foundation, 1985.
Clinical and laboratory observations Evidence of increased intrauterine bone resorption in term infants of mothers with insulin-dependent diabetes Sergio Demarini, MD, Bonny L. Specker, PhD, Rosa I. Sierra, MS, M e n a c h e m Miodovnik, Mb, and Reginald C. Tsang, MBB$ From the Perinatal Research institute, Division of Neonatology, Departments of Pediatrics and of Obstetrics and Gynecology, University of Cincinnati Medical Center, Children's Hospital Medical Center, Cincinnati, Ohio
Infants of diabetic mothers (IDMs) h a v e lower b o n e mineral content than control subjects at birth. We measured cord blood p r o p e p t i d e of type I p r o c o l l a g e n (PICP), a marker of b o n e formation, a n d t e l o p e p t i d e of type I c o l l a g e n (ICTP), a marker of b o n e resorption, in 25 term IDMs and 20 term control subjects. Concentrations of ICTP were higher in IDMs than in control subjects; there was no difference in PICP concentrations. We c o n c l u d e that osteoclastic activity a p p e a r s to be higher in IDMs than in control subjects in utero. (J PEDIATR1995;126:7968) Supported in part by the Diabetes in Pregnancy Program Project (HICHD 11725) and by a grant from the J. Miglierina Foundation, Varese, Italy (Dr. Demarini), Submitted for publication Aug. 5, 1994; accepted Nov. 14, 1994.
Reprint requests: Reginald C. Tsang, MBBS, Department of Pediatrics, University of Cincinnati Medical Center, 231 Bethesda Ave., ML 541, Cincinnati, OH 45267-0541. Copyright ® 1995 by Mosby-Year Book, Inc. 0022-3476/95/$3.00 + 0 9/24/62071