- Email: [email protected]
Rickets of prematurity: Calcium and phosphorus supplementation
FETAL A N D N E O N A T A L M E D I C I N E
Rickets of prematurity: Calcium and phosphorus supplementation Seventy-four infants weighing <1500 gm at birth werefed enterally from birth until day 47. Group A (18 infants) were given SMA Gold Cap; group B (18 infants), supplementary calcium to 21 mmol/L (84 mg/dl); group C (16 infants), further calcium supplementation to 31.2 mmol/L (125 mg/dl); and group D (22 infants), milk With calcium content 31.2 mmol/L (125 mg/dl) and phosphorus supplementation to 15.7 mmol/L (49 mg/dl). The addition of calcium reduced the radiologic evidence of rickets, and combined calcium and phosphorus supplementation maintained plasma alkaline phosphatase activity within the normal rangefor 6 weeks. (J P~DIATIe106:265, 1985)
I. A. Laing, M.A., M.R.C.P,, E. J. Glass, M.D., M.R.C.P., G. M. A. Hendry, F,R.C.R., A. Westwood, M.R.S.C., M.R,C.Path., R. A. Eiton, B.A., Ph.D., M. Lang, R.S.C.N., and R. Hume, Ph.D., M.R.C.P. Edinburgh. Scotland
RICKETS IS COMMON in preterm infants t'2 and is associated with impairment of linear growth, 3 spontaneous fractures, 4 and respiratory distress? The pathogenesis of the condition is uncertain. 6 vitamin D supplements are required by preterm infants, 7 but rickets may occur even when serum concentrations of 1,25-dihydroxycholecalciferol are normal or high. s Deficiencies in dietary calcium 9 and phosphorus ~~ have been suggested as Contributory factors. Radiographic changes may not occur until late in the disease, but plasma alkaline phosphatase activity can be measured as an early indicator of rickets of prematurity." We report the biochemical and radiologic effects on the very-low-birth-weight infant of supplementing a proprietary milk with calcium and phosphorus.
METHODS Seventy-four infants weighing <1500 gm at birth were fed enterally from birth for 47 days. For the first 5 days all From the Department of Child Life and Health, University of Edinburgh. Submitted for publication March 14. 1984; accepted July 6, 1984. Reprint requests: L Laing, M.A., M.R.C.P., Special Care Baby Unit, Simpson Memorial Maternity Pavilion, Lauriston Place, Edinburgh, Scotland.
were fed SMA Gold Cap* (Wyeth Laboratories, Philadelphia). Thereafter, sequential cohorts (groups A through D) were given formulas made by diluting SMA G01d Cap concentrate liquid with water and additive solutions:sodium chloride 5.84% wt/vol, sodium bicarbonate 8.3% wt/ vol, calcium gluconate 10% wt/vol, calcium chloride 13.4% wt/vol, potassium phosphate 17.42% wt/vol, and potassiUm chloride 15% wt/vol. The final concentrations in the formulas were sodium 26.5 mmol/L (61 mg/d!), potass ium 14.3 mmol/L (56 mg/dl), and chloride 23.8 mmol/L (!04 mg/dl); concentrations of calcium and phosphorus were varied (Table I). All infants received supplements of Vitamin D2 460 IU/day for the duration of the study. The plasma calcium and phosPhate concentrations and alkaline phosphatase activity in each infant were measured at age 5 to 10 days and in each subsequent week for 6 weeks. Plasma calcium was measured by atomic absorp tion spectrometry, ~2 and phosphate and alkaline phosphatase by spectrophotometric methods based on Phosph0molybdate reduction ~3 and 4-nitrophenylphos: phate hydrolysis, ~4respectively. Plasma calcium and phos~ phate concentrations and alkaline phosphatase activities *Major constituents:carbohydrate(lactose) 72,gin/L, protein 15 gm/L, fat 36 gin/L, sodium6.5 mmol/L(15 mg/dl), potassium1.43 mmol/L(56 mg/dl), chloride 1.13 mm01/L(45 mg/dl), vitaminD3420 IU/L.
The Journal of P E D I A T R I C S
265
266
Laing et al.
The Journal of Pediatrics February 1985
Table I. Characteristics of four groups of infants and miik formulas
Group A Group B Group C Group D
Infants (n)
Birth weight (kg) (X + 1 SB)
Gestational age (wk) ( x +_ 1SD)
Calcium content of milk (mmol/L)
Phosphorus content of milk (mmol/L)
Calcium/ phosphorus ratio
18 18 16 22
1.36 _ 0.23 1.4l _+ 0.23 1.19 _+ 0.33 1.23 + 0.17
31.1 _+ 0.9 30.2 + 1.5 29.1 _+ 2.0 29.5 + 1.7
11.0 21.0 31.2 31.2
10.7 10.5 10.7 15.7
1.0 2.0 2.9 2.0
Table lI. Variations in plasma alkaline phosphatase activity with postnatal age
Postnatal age (wk)
Group .4 (It~L)
Group B (!V/L)
Group C (IV~L)
Group D (IV~L)
1 2 3 4 5 6 7
297.3 + 64.4 393.4 + 137.1 488.2 + 240.2 470.1 + 169.8 496.0 _+ 207.1 506.9 -+ 263.2 589.5 - 280.2
281.2 _+ 71.2 289.8 + 65.0 333.1 - 79.4 317.2 + 97.3 312.6 ---+104.8 325.i + t41.3 354.9 + 168.0
260.1 -+ 60.0 328.8 _+ 146.2 356.8 _+ 135.9 377.5 _+ 124.7 385.5 + 139.1 396.2 + 152.5 416.8 _+ 152.3
287.5 --_ 119.5 260.6 -+ 102.1 253.3 + 83.7 263.9 + 91.9 258.3 + 87.7 254.9 _+ 89.9 324.0 _+ 137.4
Data representmean _+ 1 SD. Table IlL Radiologic bone change
Group A Group B Group C Group D (n=18) (n= lS) (n=16)(n=22) Normal mineralization ? Osteoporosis/normal Osteoporosis Metaphyseal change Periosteal reaction No x-ray study
2 1 8 2 l 7
8 1 1 0 0 8
13 0 2 1 0 1
19 1 2 1 0 1
were compared by analysis of variance followed by pairwise comparisons using the Student-Newman-Keuls procedure? 5 The mean daily calcium and phosphorus intakes of each infant were calculated. Radiographs were obtained in 57 infants examined routinely at 6 weeks of age. At the end of the study all radiographs were assessed independently of clinical and biochemical data by a pediatric radiologist. Bone demineralization, metaphyseal changes, and periosteal reactions were recorded." Statistical analysis of radiologic abnormality was by ehi-square test with the Yates correction comparing group A with the other three groups combined. All other statistical analysis was by Student t test. RESULTS The mean daily intakes of calcium and phosphorus increased from week 2, when supplementation began, in keeping with the extra calcium and phosphorus content of the milk (Figure). Plasma calcium and phosphate concen-
trations were measured weekly, and analysis of variance showed no significant differences among the four groups in plasma calcium at any time, but plasma phosphate showed differences at weeks 1 to 6 (P < 0.05 except for week 4 with P < 0.01). On follow-up testing, groups A, B, and C were not significantly different at any time. Group D differed from group A at weeks 4, 5, and 6, from group B at weeks 1, 2, 3, and 4, and from group C at weeks 2, 4, and 5. No differences in plasma alkaline phosphatase activity among the groups were observed during the first postnatal week (Table II). In the subsequent 6 weeks, analysis of variance showed highly significant differences in alkaline phosphatase among the four groups ( P < 0 . 0 1 or P < 0.001). Follow-up tests Showed significant differences between groups A and B and between groups A and D for all 6 weeks, and also between groups A and C at 3, 4, 5, and 7 weeks and groups C and D at weeks 4, 5, and 6. No differences between groups B and C nor between groups B and D were evident. In addition, plasma alkaline phosphatase activity was compared with gestational age values previously eStablished in our uniP~; groups A, B, and C had significantly elevated levels from 33 postmenstrual weeks until the end of the study, but the mean for group D was not significantly raised until the last week of the study period. No radiologic differences were identified among groups B, C, and D, but group A had a significantly higher incidence of radiologic abnormalities (P < 0.001) (Table
Volume 106 Number 2
Rickets o f prematurity
6-
GROUP GROUP
5-
MEAN CALCIUM INTAKE
GROUP q-
mmol/Kg/day 3"
GROUPA 2"
1
WEEKS 3.5
3.0
2,5 MEAN PHOSPHORUS INTAKE 2,0
,,,L~r~'------"~r~~
/ I
GROUPD
I
I
/ ## / ~ # ,/~ . ~ . , . .
....9 GROUP ..........m.........." ~ ' ~ GROUPB . ~ . . ~ . . ~ . . ,..~ ~ 0 GROUPA
mmol/Kg/day
1.5-
1.0-
267
phosphorus retained by the fetus in the intrauterine environment varies through the last trimester, :2 but it is not known whether preterm infant requirements change in a similar manner. Our data demonstrate that calcium supplementation of a low-solute milk can prevent the radiologic changes of rickets in preterm infants, thus confirming previous findings using radiodensitometric methods and cortical thickness as a means of studying bone formation.9 However, radiologic and densitometric methods may lack precision in the study of bone mineralization," and in our study, infants fed milk supplemented only with calcium still had increased plasma alkaline phosphatase activity. The further addition of phosphorus maintains plasma alkaline phosphatase values within normal limits for gestational age. u These results complement the observation of Steichen et al., 1~who, using a similar calcium and phosphorus supplemented milk, showed extrauterine bone mineralization analyzed by direct photon absorptiometry to approximate intrauterine bone mineralization. Our study demonstrates that rickets of prematurity is largely preventable, but further work is required to define the precise nutritional requirements for appropriate bone growth in the preterm infant. REFERENCES
0.5
i
i
1
2
t 3
i 4
I
i
1
5
6
7
WEEKS
Figure. Mean calcium and phosphorus intakes for each week of study.
III). Individuals with metaphyseal change or periosteal reaction invariably had osteoporosis also. DISCUSSION The calcium and phosphorus content of low-solute formulas based on the composition of mature human milk cannot meet the requirements of the preterm infant if accretion of these dements is to continue at intrauterine rates.;6, J7 Calcium retention increases with the amount of calcium ingested) 8 and with high calcium intake can be greater in preterm infants than occurs in utero. 9 Phosphorus supplementation improves calcium retention in preterm infants fed human milkJ 9 The varieties of calcium and phosphorus content as well as calcium/phosphorus ratio of formulas for LBW infants emphasize the lack of consensus on their nutritional requirements. Absorption of calcium is influenced by postnatal age, ~7endogenous intestinal secretion,2~ fat absorption,2~ metabolism of vitamin D, 3 and calcium/phosphorus ratio. 22The ratio of calcium/
1. Von Sydow G: A study of the development of rickets in premature infants. Acta Paediatr Scand [Suppl] 33(suppl 2):1, 1946. 2. Kulkarni PB, Hall RT, Rhodes PG: Rickets in very-lowbirth-weight infants. J PEDIATR96:249, 1980. 3. Hillman LS, Huebener DV, Haddad JC: Long-term effects of low 25-hydroxyvitaminD serum concentration in premature infants: A preliminary report. Vitamin D basic research and its clinical application. Berlin, 1979, Walter de Gruyter, p 33. 4. Geggel RL, Pereira GR, Spaekman TJ: Fractured ribs: Unusual presentation of rickets in premature infants. J PEDIATR93:680, 1978. 5. GlasgowJFT, Thomas PS: Rachitic respiratory distress in small preterm infants. Arch Dis Child 52:268, 1977. 6. Brooke OG: Supplementary vitamin D in infancy and childhood. Arch Dis Child 58:573, 1983. 7. American Academy of Pediatrics Committee on Nutrition: Vitamin and mineral supplement needs in normal children in the United States. Pediatrics 66:1015, 1980. 8. Steichen J J, Tsang RC, Greer FR, Ho M, Hug G: Elevated serum 1,25-dihydroxyvitaminD concentrations in rickets of very-low-birth-weightinfants. J PEDIATR99:293, 1981. 9. Day GM, Chance GW, Raddle IC, Reilly BJ, Park E, Sheepers J: Growth and mineral metabolism in very low birthweight infants. IL Effects of calcium supplementationon growth and divalent cations. Pediatr Res 9:568, 1975. 10. Steichen J J, Gratton PAC, Tsang RC: Osteopenia of prematurity: The cause and possible treatment. J PEDtATR96:528, 1980. 11. Glass EJ, Hume R, Hendry GMA, Strange RC, Forfar JO:
26 8
12.
13.
14.
15. 16. 17.
18.
Laing et al.
Plasma alkaline phosphatase activity in rickets of prematurity. Arch Dis Child 57:373, 1982. Cali JP, Gambino SR, Young DS: A referee method for the determination of calcium in serum. Clin Chem 19:1208, 1973. Gindler EM, Ishinzaki RT: Rapid semimicrocolorimetric determination of phosphorus in serum and nonionic surfactants. Clin Chem 15:807, 1969. Morgenstern S, Kessler G, Auerback J, Flor RV, Klein B: An automated P-nitrophenylphosphate serum alkaline phosphatase procedure for the AutoAnalyser. Clin Chem 11:876, 1965. Sokal RR, Rohlf FJ: Biometry. San Francisco, 1969, WH Freeman, p 235. Stearns G: The mineral metabolism of normal infants. Physiol Rev 19:415, 1939. Shaw JCL: Evidence for defective skeletal mineralization in low birthweight infants: The absorption of calcium and fat. Pediatrics 57:16, 1976. Barltrop D, Oppe TE: Calcium and fat absorption by low
The Journal of Pediatrics February 1985
19.
20.
21.
22.
23. 24.
birthweight infants t?om a calcium-supplemented milk formula. Arch Dis Child 48:580, 1973. Senterre J, Putet G, Salle B, Rigo J: Effects of vitamin D and phosphorus supplementation on calcium retention in preterrn infants fed banked human milk. J PEDIATR 103:304, 1983. Barltrop D, Oppe TE: Absorption of fat and calcium by low birthweight infants from milks containing butter fat and olive oil. Arch Dis Child 48:496, 1973. Widdowson EM: Absorption and excretion of fat, nitrogen and minerals from "filled" milks by babies one week old. Lancet 2:1099, 1965. Moya M, Domenech E: Role of calcium-phosphate ratio of milk formulas on calcium balance in low birthweight infants during the first 3 days of life. Pediatr Res 16:675, 1982. Ziegler EE, O'Donnel AM, Nelson SE, Fomon S J: Body composition of the reference fetus. Growth 40:324, 1976. Lachmann E. Osteoporosis: Potentialities and limitations of its roentgenologic diagnosis. Am J Roentgenol 74:712, 1955.
Rickets of prematurity: Calcium and phosphorus supplementation Seventy-four infants weighing <1500 gm at birth werefed enterally from birth until day 47. Group A (18 infants) were given SMA Gold Cap; group B (18 infants), supplementary calcium to 21 mmol/L (84 mg/dl); group C (16 infants), further calcium supplementation to 31.2 mmol/L (125 mg/dl); and group D (22 infants), milk With calcium content 31.2 mmol/L (125 mg/dl) and phosphorus supplementation to 15.7 mmol/L (49 mg/dl). The addition of calcium reduced the radiologic evidence of rickets, and combined calcium and phosphorus supplementation maintained plasma alkaline phosphatase activity within the normal rangefor 6 weeks. (J P~DIATIe106:265, 1985)
I. A. Laing, M.A., M.R.C.P,, E. J. Glass, M.D., M.R.C.P., G. M. A. Hendry, F,R.C.R., A. Westwood, M.R.S.C., M.R,C.Path., R. A. Eiton, B.A., Ph.D., M. Lang, R.S.C.N., and R. Hume, Ph.D., M.R.C.P. Edinburgh. Scotland
RICKETS IS COMMON in preterm infants t'2 and is associated with impairment of linear growth, 3 spontaneous fractures, 4 and respiratory distress? The pathogenesis of the condition is uncertain. 6 vitamin D supplements are required by preterm infants, 7 but rickets may occur even when serum concentrations of 1,25-dihydroxycholecalciferol are normal or high. s Deficiencies in dietary calcium 9 and phosphorus ~~ have been suggested as Contributory factors. Radiographic changes may not occur until late in the disease, but plasma alkaline phosphatase activity can be measured as an early indicator of rickets of prematurity." We report the biochemical and radiologic effects on the very-low-birth-weight infant of supplementing a proprietary milk with calcium and phosphorus.
METHODS Seventy-four infants weighing <1500 gm at birth were fed enterally from birth for 47 days. For the first 5 days all From the Department of Child Life and Health, University of Edinburgh. Submitted for publication March 14. 1984; accepted July 6, 1984. Reprint requests: L Laing, M.A., M.R.C.P., Special Care Baby Unit, Simpson Memorial Maternity Pavilion, Lauriston Place, Edinburgh, Scotland.
were fed SMA Gold Cap* (Wyeth Laboratories, Philadelphia). Thereafter, sequential cohorts (groups A through D) were given formulas made by diluting SMA G01d Cap concentrate liquid with water and additive solutions:sodium chloride 5.84% wt/vol, sodium bicarbonate 8.3% wt/ vol, calcium gluconate 10% wt/vol, calcium chloride 13.4% wt/vol, potassium phosphate 17.42% wt/vol, and potassiUm chloride 15% wt/vol. The final concentrations in the formulas were sodium 26.5 mmol/L (61 mg/d!), potass ium 14.3 mmol/L (56 mg/dl), and chloride 23.8 mmol/L (!04 mg/dl); concentrations of calcium and phosphorus were varied (Table I). All infants received supplements of Vitamin D2 460 IU/day for the duration of the study. The plasma calcium and phosPhate concentrations and alkaline phosphatase activity in each infant were measured at age 5 to 10 days and in each subsequent week for 6 weeks. Plasma calcium was measured by atomic absorp tion spectrometry, ~2 and phosphate and alkaline phosphatase by spectrophotometric methods based on Phosph0molybdate reduction ~3 and 4-nitrophenylphos: phate hydrolysis, ~4respectively. Plasma calcium and phos~ phate concentrations and alkaline phosphatase activities *Major constituents:carbohydrate(lactose) 72,gin/L, protein 15 gm/L, fat 36 gin/L, sodium6.5 mmol/L(15 mg/dl), potassium1.43 mmol/L(56 mg/dl), chloride 1.13 mm01/L(45 mg/dl), vitaminD3420 IU/L.
The Journal of P E D I A T R I C S
265
266
Laing et al.
The Journal of Pediatrics February 1985
Table I. Characteristics of four groups of infants and miik formulas
Group A Group B Group C Group D
Infants (n)
Birth weight (kg) (X + 1 SB)
Gestational age (wk) ( x +_ 1SD)
Calcium content of milk (mmol/L)
Phosphorus content of milk (mmol/L)
Calcium/ phosphorus ratio
18 18 16 22
1.36 _ 0.23 1.4l _+ 0.23 1.19 _+ 0.33 1.23 + 0.17
31.1 _+ 0.9 30.2 + 1.5 29.1 _+ 2.0 29.5 + 1.7
11.0 21.0 31.2 31.2
10.7 10.5 10.7 15.7
1.0 2.0 2.9 2.0
Table lI. Variations in plasma alkaline phosphatase activity with postnatal age
Postnatal age (wk)
Group .4 (It~L)
Group B (!V/L)
Group C (IV~L)
Group D (IV~L)
1 2 3 4 5 6 7
297.3 + 64.4 393.4 + 137.1 488.2 + 240.2 470.1 + 169.8 496.0 _+ 207.1 506.9 -+ 263.2 589.5 - 280.2
281.2 _+ 71.2 289.8 + 65.0 333.1 - 79.4 317.2 + 97.3 312.6 ---+104.8 325.i + t41.3 354.9 + 168.0
260.1 -+ 60.0 328.8 _+ 146.2 356.8 _+ 135.9 377.5 _+ 124.7 385.5 + 139.1 396.2 + 152.5 416.8 _+ 152.3
287.5 --_ 119.5 260.6 -+ 102.1 253.3 + 83.7 263.9 + 91.9 258.3 + 87.7 254.9 _+ 89.9 324.0 _+ 137.4
Data representmean _+ 1 SD. Table IlL Radiologic bone change
Group A Group B Group C Group D (n=18) (n= lS) (n=16)(n=22) Normal mineralization ? Osteoporosis/normal Osteoporosis Metaphyseal change Periosteal reaction No x-ray study
2 1 8 2 l 7
8 1 1 0 0 8
13 0 2 1 0 1
19 1 2 1 0 1
were compared by analysis of variance followed by pairwise comparisons using the Student-Newman-Keuls procedure? 5 The mean daily calcium and phosphorus intakes of each infant were calculated. Radiographs were obtained in 57 infants examined routinely at 6 weeks of age. At the end of the study all radiographs were assessed independently of clinical and biochemical data by a pediatric radiologist. Bone demineralization, metaphyseal changes, and periosteal reactions were recorded." Statistical analysis of radiologic abnormality was by ehi-square test with the Yates correction comparing group A with the other three groups combined. All other statistical analysis was by Student t test. RESULTS The mean daily intakes of calcium and phosphorus increased from week 2, when supplementation began, in keeping with the extra calcium and phosphorus content of the milk (Figure). Plasma calcium and phosphate concen-
trations were measured weekly, and analysis of variance showed no significant differences among the four groups in plasma calcium at any time, but plasma phosphate showed differences at weeks 1 to 6 (P < 0.05 except for week 4 with P < 0.01). On follow-up testing, groups A, B, and C were not significantly different at any time. Group D differed from group A at weeks 4, 5, and 6, from group B at weeks 1, 2, 3, and 4, and from group C at weeks 2, 4, and 5. No differences in plasma alkaline phosphatase activity among the groups were observed during the first postnatal week (Table II). In the subsequent 6 weeks, analysis of variance showed highly significant differences in alkaline phosphatase among the four groups ( P < 0 . 0 1 or P < 0.001). Follow-up tests Showed significant differences between groups A and B and between groups A and D for all 6 weeks, and also between groups A and C at 3, 4, 5, and 7 weeks and groups C and D at weeks 4, 5, and 6. No differences between groups B and C nor between groups B and D were evident. In addition, plasma alkaline phosphatase activity was compared with gestational age values previously eStablished in our uniP~; groups A, B, and C had significantly elevated levels from 33 postmenstrual weeks until the end of the study, but the mean for group D was not significantly raised until the last week of the study period. No radiologic differences were identified among groups B, C, and D, but group A had a significantly higher incidence of radiologic abnormalities (P < 0.001) (Table
Volume 106 Number 2
Rickets o f prematurity
6-
GROUP GROUP
5-
MEAN CALCIUM INTAKE
GROUP q-
mmol/Kg/day 3"
GROUPA 2"
1
WEEKS 3.5
3.0
2,5 MEAN PHOSPHORUS INTAKE 2,0
,,,L~r~'------"~r~~
/ I
GROUPD
I
I
/ ## / ~ # ,/~ . ~ . , . .
....9 GROUP ..........m.........." ~ ' ~ GROUPB . ~ . . ~ . . ~ . . ,..~ ~ 0 GROUPA
mmol/Kg/day
1.5-
1.0-
267
phosphorus retained by the fetus in the intrauterine environment varies through the last trimester, :2 but it is not known whether preterm infant requirements change in a similar manner. Our data demonstrate that calcium supplementation of a low-solute milk can prevent the radiologic changes of rickets in preterm infants, thus confirming previous findings using radiodensitometric methods and cortical thickness as a means of studying bone formation.9 However, radiologic and densitometric methods may lack precision in the study of bone mineralization," and in our study, infants fed milk supplemented only with calcium still had increased plasma alkaline phosphatase activity. The further addition of phosphorus maintains plasma alkaline phosphatase values within normal limits for gestational age. u These results complement the observation of Steichen et al., 1~who, using a similar calcium and phosphorus supplemented milk, showed extrauterine bone mineralization analyzed by direct photon absorptiometry to approximate intrauterine bone mineralization. Our study demonstrates that rickets of prematurity is largely preventable, but further work is required to define the precise nutritional requirements for appropriate bone growth in the preterm infant. REFERENCES
0.5
i
i
1
2
t 3
i 4
I
i
1
5
6
7
WEEKS
Figure. Mean calcium and phosphorus intakes for each week of study.
III). Individuals with metaphyseal change or periosteal reaction invariably had osteoporosis also. DISCUSSION The calcium and phosphorus content of low-solute formulas based on the composition of mature human milk cannot meet the requirements of the preterm infant if accretion of these dements is to continue at intrauterine rates.;6, J7 Calcium retention increases with the amount of calcium ingested) 8 and with high calcium intake can be greater in preterm infants than occurs in utero. 9 Phosphorus supplementation improves calcium retention in preterm infants fed human milkJ 9 The varieties of calcium and phosphorus content as well as calcium/phosphorus ratio of formulas for LBW infants emphasize the lack of consensus on their nutritional requirements. Absorption of calcium is influenced by postnatal age, ~7endogenous intestinal secretion,2~ fat absorption,2~ metabolism of vitamin D, 3 and calcium/phosphorus ratio. 22The ratio of calcium/
1. Von Sydow G: A study of the development of rickets in premature infants. Acta Paediatr Scand [Suppl] 33(suppl 2):1, 1946. 2. Kulkarni PB, Hall RT, Rhodes PG: Rickets in very-lowbirth-weight infants. J PEDIATR96:249, 1980. 3. Hillman LS, Huebener DV, Haddad JC: Long-term effects of low 25-hydroxyvitaminD serum concentration in premature infants: A preliminary report. Vitamin D basic research and its clinical application. Berlin, 1979, Walter de Gruyter, p 33. 4. Geggel RL, Pereira GR, Spaekman TJ: Fractured ribs: Unusual presentation of rickets in premature infants. J PEDIATR93:680, 1978. 5. GlasgowJFT, Thomas PS: Rachitic respiratory distress in small preterm infants. Arch Dis Child 52:268, 1977. 6. Brooke OG: Supplementary vitamin D in infancy and childhood. Arch Dis Child 58:573, 1983. 7. American Academy of Pediatrics Committee on Nutrition: Vitamin and mineral supplement needs in normal children in the United States. Pediatrics 66:1015, 1980. 8. Steichen J J, Tsang RC, Greer FR, Ho M, Hug G: Elevated serum 1,25-dihydroxyvitaminD concentrations in rickets of very-low-birth-weightinfants. J PEDIATR99:293, 1981. 9. Day GM, Chance GW, Raddle IC, Reilly BJ, Park E, Sheepers J: Growth and mineral metabolism in very low birthweight infants. IL Effects of calcium supplementationon growth and divalent cations. Pediatr Res 9:568, 1975. 10. Steichen J J, Gratton PAC, Tsang RC: Osteopenia of prematurity: The cause and possible treatment. J PEDtATR96:528, 1980. 11. Glass EJ, Hume R, Hendry GMA, Strange RC, Forfar JO:
26 8
12.
13.
14.
15. 16. 17.
18.
Laing et al.
Plasma alkaline phosphatase activity in rickets of prematurity. Arch Dis Child 57:373, 1982. Cali JP, Gambino SR, Young DS: A referee method for the determination of calcium in serum. Clin Chem 19:1208, 1973. Gindler EM, Ishinzaki RT: Rapid semimicrocolorimetric determination of phosphorus in serum and nonionic surfactants. Clin Chem 15:807, 1969. Morgenstern S, Kessler G, Auerback J, Flor RV, Klein B: An automated P-nitrophenylphosphate serum alkaline phosphatase procedure for the AutoAnalyser. Clin Chem 11:876, 1965. Sokal RR, Rohlf FJ: Biometry. San Francisco, 1969, WH Freeman, p 235. Stearns G: The mineral metabolism of normal infants. Physiol Rev 19:415, 1939. Shaw JCL: Evidence for defective skeletal mineralization in low birthweight infants: The absorption of calcium and fat. Pediatrics 57:16, 1976. Barltrop D, Oppe TE: Calcium and fat absorption by low
The Journal of Pediatrics February 1985
19.
20.
21.
22.
23. 24.
birthweight infants t?om a calcium-supplemented milk formula. Arch Dis Child 48:580, 1973. Senterre J, Putet G, Salle B, Rigo J: Effects of vitamin D and phosphorus supplementation on calcium retention in preterrn infants fed banked human milk. J PEDIATR 103:304, 1983. Barltrop D, Oppe TE: Absorption of fat and calcium by low birthweight infants from milks containing butter fat and olive oil. Arch Dis Child 48:496, 1973. Widdowson EM: Absorption and excretion of fat, nitrogen and minerals from "filled" milks by babies one week old. Lancet 2:1099, 1965. Moya M, Domenech E: Role of calcium-phosphate ratio of milk formulas on calcium balance in low birthweight infants during the first 3 days of life. Pediatr Res 16:675, 1982. Ziegler EE, O'Donnel AM, Nelson SE, Fomon S J: Body composition of the reference fetus. Growth 40:324, 1976. Lachmann E. Osteoporosis: Potentialities and limitations of its roentgenologic diagnosis. Am J Roentgenol 74:712, 1955.