During the last trimester of pregnancy, there is a sixfold increase in fetal calcium and phosphorus accumulation. Unsupplemented human breast milk may not provide sufficient calcium and phosphorus for the rapdily growing preterm infant to match the accumulation that should have taken place in utero and to permit normal bone mineralization.
Rickets of prematurity may present clinically between the 6th and 12th postnatal week. The clinical diagnosis may be confirmed using simple biochemical tests. Inadequate mineral substrate intake, particularly of phosphorus, is the most common cause, although a delay in the maturation of the renal enzyme, 1-α hydroxylase, with low plasma concentrations of 1,25-dihydroxyvitamin D, may also occur. The biochemical response to treatment can be determined by documenting a fall in plasma alkaline phosphatase activity and a rise in plasma phosphate concentration and urinary phosphate excretion.
MacFarlaneAColeSJohnsonABoltingB. Epidemiology of birth before 28 weeks of gestation. Br Med Bull1988; 44: 861–93.
2.
MawerEB. Clinical implications of measurements of circulating Vitamin D metabolites. Clin Endocrinol Metab1980; 9: 63–79.
3.
RaiszLGTrummelCLHolickMFDeLucaHF. 1,25-dihydroxycholecalciferol: A potent stimulator of bone resorption in tissue culture. Science1972; 175: 768–9.
4.
DekelSSalamaREdelsteinS. The effect of Vitamin D and its metabolites on fracture repair in chicks. Clin Sci1983; 65: 429–36.
5.
KanisJACundyTBartlettM. Is 24,25-dihydroxycholecalciferol a calcium regulating hormone in man?Br Med J1978; 1: 1382–6.
6.
GarabedianMTanakaYHolickMFDeLucaHF. Response of intestinal calcium transport and bone calcium mobilization to 1,25-dihydroxyvitamin D3 in thyroparathyroidectomized rats. Endocrinology1974; 94: 1022–7.
7.
EraserDR. Regulation of the metabolism of Vitamin D. Physiol Rev1980; 60: 551–613.
8.
ReitzREDaaneTAWoodsJRWeinsteinRL. Calcium, magnesium, phosphorus and parathyroid hormone interrelationships in pregnancy and newborn infants. Obstet Gynecol1977; 50: 701–5.
9.
SpanosEPikeJWHausslerMR. Circulating 1–25-dihydroxyvitamin D in the chicken: Enhancement by injection of prolactin and during egg laying. Life Sci1976; 19: 1751–6.
10.
BrownDJSpanosEMacIntyreI. Role of pituitary hormones in regulating renal Vitamin D metabolism in man. Br Med J1980; 280: 277–8.
11.
HeaneyRPSkillmanTG. Calcium metabolism in normal human pregnancy. J Clin Endocrinol1971; 33: 661–70.
12.
ReddyGSNormanAWWillisDM. Regulation of Vitamin D metabolism in normal human pregnancy. J Clin Endocrinol Metab1983; 56: 363–70.
13.
WhiteheadMLaneGYoungO. Interrelations of calcium-regulating hormones during normal pregnancy. Br Med J1981; 283: 10–12.
14.
WeismanYHarellAEdelsteinS. 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D3in vitro synthesis by human decidua and placenta. Nature1979; 281: 317–19.
15.
WhitsettJAHoMTsangRCNormanEJAdamsKG. Synthesis of 1,25-dihydroxyvitamin D3 by human placentain vitro. J. Clin Endocrinol Metab1981; 53: 484–484.
16.
KumarRCohenWRSilvaPEpsteinFH. Elevated 1,25-dihydroxyvitamin D plasma levels in normal human pregnancy and lactation. J Clin Invest1979; 63: 342–4.
17.
TurtonCWGStampTCBStanleyPMaxwellJD. Altered Vitamin D metabolism in pregnancy. Lancet1977; i: 222–4.
18.
DentCEGuptaMM. Plasma 25-hydroxyvitamin D levels during pregnancy in Caucasians and in vegetarian and non-vegetarian Asians. Lancet1975; ii: 1057–60.
19.
WhiteheadMLaneGYoungO. Interrelationships of calcium-regulating hormones during pregnancy. Br Med J1981; 3: 10–13.
20.
DrakeTSKaplanRALewisTA. The physiologic hyperparathyroidism of pregnancy. Is it primary or secondary?Obstet & Gynaecol1979; 53: 746–9.
21.
KerrCLokenHFGlendeningMB. Calcium and phosphorus dynamics in pregnancy. Am J Obstet Gynecol1963; 83: 2–8.
22.
LamkeBBrudenJMobergP. Changes in bone mineral content during pregnancy and lactation. Acta Obstet Gynecol Stand1977; 56: 217–19.
23.
RambergCFDelivoria-PapadopoulosMCrandallEJ. Kinetic analysis of calcium transport across the placenta. J Appl Physiol1973; 35: 682–8.
24.
MacDonaldNSHutchinsonDLHeplerMFlynnE. Movement of calcium in both directions across the primate placenta. Proc Soc Exp Biol Med1965; 119: 476–81.
25.
WhitsettJATsangRC. Calcium uptake and binding by membrane functions of human placenta: ATP-dependent calcium accumulation. Pediatr Res1980; 14: 769–75.
MonizCFNicolaidesKHTzannatosCRodeckCH. Calcium homeostasis in second trimester fetuses. J Clin Pathol1986; 39: 838–41.
28.
HaddadJGBoisseauVAvioliLV. Placental transfer of Vitamin D3 and 25-hydroxycholecalciferol in the rat. J Lab Clin Med1971; 77: 908–15.
29.
HillmanLSHaddadJG. Human perinatal Vitamin D metabolism, 25 hydroxyvitamin D in maternal and cord blood. J Pediatr1974; 84: 742–9.
30.
BouillonRVan BaelenHDe MoorP. 25 hydroxyvitamin D and its binding protein in maternal and cord serum. J Clin Endocrinol Metab1977; 45: 679–84.
31.
SteichenJJTsangRCGrattonTLHamstraADeLucaHF. Vitamin D homeostasis in the perinatal period: 1,25 Dihydroxyvitamin D in maternal cord and neonatal blood. N Engl J Med1980; 302: 315–19.
32.
FleischmanARRosenJFColeJSmithCMDeLucaHF. Maternal and foetal serum 1,25-dihydroxyvitamin D levels at term. J. Pediatr1980; 97: 640–2.
33.
MarxSJSwartEGHamstraAJDeLucaHF. Normal intrauterine development of the fetus of a woman receiving extraordinarily high doses of 1,25-dihydroxyvitamin D3. J Clin Endocrinol Metab1980; 51: 1138–42.
34.
KuoppalaTTuimalaRParviainenMKoskinenT. Can the fetus regulate its calcium uptake. Br J Obst Gyn1984; 91: 1192–6.
35.
MooreESLangmanCBFavusMJCoeFL. Role of foetal 1,25-dihydroxyvitamin D production in intrauterine phosphorus and calcium homeostasis. Pediatr Res1985; 19: 566–9.
36.
NorthropGMisenheimerHRBeckerFO. Failure of parathyroid hormone to cross the nonhuman primate placenta. Am J Obstet Gynecol1977; 129: 449–53.
37.
ScothorneRJ. Functional capacity of foetal parathyroid glands with reference to their clinical use as homografts. Ann NY Acad Sci1964; 120: 669–76.
38.
DelvinEGlorieuxFSalleBDavidLVerenneJ. Control of Vitamin D metabolism in preterm infants fetomaternal relationships. Arch Dis Child1982; 57: 754–7.
39.
SchedewieHKOdellWDFisherDA. Parathormone and perinatal calcium homeostasis. Pediatr Res1979; 13: 1–6.
40.
AllgroveJAdamiSManningRMO'RiordanJLM. Cytochemical bioassay of parathyroid hormone in maternal and cord blood. Arch Dis Child1985; 60: 110–15.
41.
HillmanLSRojanasthitSSlatopolskyHaddadJG. Serial measurements of serum calcium, magnesium, parathyroid hormone, calcitonin and 25-hydroxyvitamin D in premature and term infants during the first week of life. Pediatr Res1977; 11: 739–44.
42.
TsangRCChenIWFriedmanMAChenI. Neonatal parathyroid function: Role of gestational age and postnatal age. J Pediatr1973; 83: 728–37.
43.
NoguchiAErenMTsangRC. PTH in hypocalcemia and normocalcemia infants of diabetic mothers. J Pediatr1980; 97: 112–14.
44.
TsangRCChenIWAtkinsonW. Neonatal hypocalcemia in birth asphyxia. J. Pediatr1978; 84: 428–33.
45.
BergmanLKjellmerISelstamU. Calcitonin and parathyroid hormone-relation to early neonatal hypocalcemia in infants of diabetic mothers. Biol Neonate1974; 24: 151–60.
46.
HillmanLSHaddadJG. Perinatal Vitamin D metabolism II: Serial 25-hydroxyvitamin D concentrations in sera of term and preterm infants. J Pediatr1975; 86: 928–35.
47.
MawerEBStanburySWRobinsonMJJamesJCloseC. Vitamin D nutrition and Vitamin D metabolism in the premature human neonate. Clin Endocrinol1986; 25: 641–9.
48.
SeinoYIshiiTShimotsujiTIshidaMYabuvchiH. Plasma active Vitamin D concentration in low-birth-weight infants with rickets and its response to Vitamin D treatment. Arch Dis Child1981; 51: 628–32.
49.
SalleBLDavidLGlorieuxFHDelvinESentenceJRenaudH. Early oral administration of Vitamin D and its metabolites in premature neonates. Effect on mineral homeostasis. Pediatr Res1981; 16: 75–8.
50.
GlorieuxFHSalleBLDelvinEEDavidL. Vitamin D metabolism in preterm infants: Serum calcitriol values during the first five days of life. J Pediatr1981; 99: 640–3.
51.
KovarIZMaynePDJamesJABarnesIC. Vitamin D concentrations after oral administration of active metabolites to low birthweight infants. Arch Dis Child1986; 61: 795–7.
52.
ConcelaLLe BoulchNMiravetL. Relationship between the Vitamin D content of maternal milk and the Vitamin D status of nursing women and breast fed infants. J Endocrinol1986; 110: 43–50.
53.
MarkestadTAksnesLFinnePHAarksogD. Plasma concentrations of Vitamin D metabolites in premature infants. Pediatr Res1984; 18: 269–72.
54.
SteichenJJTsangRCGreerFRHoMHugG. Elevated serum 1,25-dihydroxyvitamin D concentrations in rickets of very-low-birth-weight infants. J Pediatr1981; 99: 293–8.
55.
ForbesGB. Calcium accumulation by the human fetus. Pediatr1976; 57: 976–7.
56.
ZieglerEEO'DonnellAMNelsonSE. Body composition of reference fetus. Growth1976; 40: 329–41.
57.
BarltropDHillierR. Calcium and phosphorus content of transitional and mature human milk. Acta Paediatr Scand1974; 63: 347–50.
58.
PiccianoMFCalkinsEJGarrickJRDeeringRH. Milk and mineral intakes in breast fed infants. Acta Paediatr Scand1981; 70: 189–94.
59.
BenjaminHRGordonHMarplesE. Calcium and phosphorus requirements of premature infants. Am J Dis Child1943; 65: 412–25.
60.
AtkinsonSA. Calcium and phosphorus requirements of low birth weight infants: A nutritional and endocrinological perspective. Nutr Rev1983; 41: 69–78.
61.
LyonAJMcIntoshN. Calcium and phosphorus balance in extremely low birthweight infants in the first six weeks of life. Arch Dis Child1984; 59: 1145–50.
62.
SuttonABarltropD. Absorption, accretion and endogenous fecal excretion of calcium by newborn infants. Nature1973; 242: 265.
63.
SenterreJPutetGSalleBRigoJ. Effects of Vitamin D and phosphorus supplementation on calcium retention in preterm infants fed banked human milk. J Pediatr1983; 103: 305–7.
64.
SteichenJJGrattonTLTsangRC. Osteopenia of prematurity: The cause and possible treatment. J Pediatr1980; 96: 528–34.
65.
KovarIZMaynePD. Unpublished observations.
66.
KovarIZMaynePDRobbéI. Hypophosphataemic rickets in the preterm infant: Hypocalcaemia after calcium and phosphorus supplementation, Arch Dis Child1983; 58: 629–629.
67.
HufriagleKPennDWilliamsP. Renal calcifications: A complication of long-term high dose furosemide. J Pediatr1978; 93: 314–15.
GriscomNCraigJNeuhauserE. Systemic bone disease developing in small premature infants. Pediatr1971; 48: 883–95.
70.
OppenheimerSSnodgrassG. Neonatal rickets. Histopathology and quantitative bone changes. Arch Dis Child1980; 55: 945–9.
71.
ThakkerRVO'RiordanJLH. Inherited forms of rickets and osteomalacia. Clin Endocrinol Metab1988; 2: 157–91.
72.
Von SydowG. A study of the development of rickets in premature infants. Acta Pediatr Scand1946; 33: 1–122.
73.
KulbarniPBHallRTRhodesPS. Rickets in very low birthweight infants. J Pediatr1980; 96: 249–52.
74.
CallenbachJCSheehanMBAbramsonSJHallRT. Etiological factors in rickets of very low birthweight infants. J Pediatr1981; 98: 800–5.
75.
JamesJRCongdonPJTruscottJHorsmanAArthurR. Osteopenia of prematurity. Arch Dis Child1986; 61: 871–6.
76.
KovarIMayneP. Plasma alkaline phosphatase activity in the preterm neonate. Acta Pediatr Scand1981; 70: 501–6.
77.
GlasgowJFTThomasPS. Rachitic respiratory distress in small preterm infants. Arch Dis Child1977; 52: 268–73.
78.
GeggelRLPereiraGRSpackmanTJ. Fractured ribs: Unusual presentation of rickets of premature infants. J Pediatr1978; 93: 680–2.
79.
BrokeOGLucasA. Metabolic bone disease in preterm infants. Arch Dis Child1985; 60: 682–5.
80.
McIntoshN. Rickets of prematurity. Bone1984; 1: 26–7.
81.
HollandPCWilkinsonARDiezJLindsellDRM. Prenatal deficiency of phosphate, phosphate supplementation, and rickets in very-low birthweight infants. Lancet1990; i: 697–701.
82.
CroftonPMHumeR. Alkaline phosphatase isoenzymes in the plasma of preterm and term infants: Serial measurements and clinical correlations. Clin Chem1987; 33: 1783–7.
83.
KovarIMaynePBarltropD. Plasma alkaline phosphatase activity: A screening test for rickets in preterm neonates. Lancet1982; i: 308–10.
84.
ClarkeLCBeckE. Plasma alkaline phosphatase activity. I. Normative data for growing children. J Pediatr1950; 36: 335–41.
85.
KrabbéSChristiansenRRobdroPTronsbolI. Pubertal growth as reflected by simultaneous changes in bone mineral content and serum alkaline phosphatase. Acta Pediatr Stand1980; 69: 49–52.
86.
SmithJ. Plasma phosphatase in rickets and other disorders of growth. Arch Dis Child1933; 8: 315–20.
87.
JamesJAMaynePDBarnesICKovarIZ. Growth velocity and plasma alkaline phosphatase activity in the preterm infant. Early Hum Dev1985; 11: 27–32.
88.
GlassEJHumeRHendryGMAStrangeRCForfarJO. Plasma alkaline phosphatase activity in rickets of prematurity. Arch Dis Child1982; 57: 373–6.
89.
WaltersEGMurphyJFHenryPGrayOPElderGH. Plasma alkaline phosphatase activity and its relation to rickets in pre-term infants. Ann Clin Biochem1986; 23: 652–6.
90.
EekSGabrielsenLHHalvorsenS. Prematurity and rickets. Pediatr1957; 20: 63–77.
CroftonPM. What is the cause of benign transient hyperphosphatasemia? A study of 35 cases. Clin Chem1988; 34: 335–40.
93.
Anon. Metabolic bone disease of prematurity. Lancet1987; i: 200.
94.
RoweJCWoodDHRoweDWRaiszLG. Nutritional hypophosphataemic rickets in a premature infant fed breast milk. N Engl J Med1979; 300: 293–6.
95.
KoohSWFraserDReillyBJHamiltonJRGallDGBellL. Rickets due to calcium deficiency. N Engl J Med1977; 297: 1264–6.
96.
BrookeOGLucasA. Metabolic bone disease in preterm infants. Arch Dis Child1985; 60: 682–5.
97.
LeaggeLLValaesT. Rickets in low birth weight infants receiving total parenteral nutrition. J Pediatr Surg1976; 11: 665–74.
98.
TheTSKolleeLAABoonJMMonnensLAH. Rickets in a preterm infant during intravenous alimentation. Acta Pediatr Scand1983; 72: 769–71.
99.
GreerFRSteichenJJTsangRC. Calcium and phosphate supplements in breast milk related rickets. Am J Dis Child1982; 136: 581–3.
100.
DaviesDP. Adequacy of expressed breast milk for early growth of preterm infants. Arch Dis Child 197; 52: 291–291.
101.
GrossSJ. Growth and biochemical response of preterm infants fed human milk or modified infant formula. N Engl J Med1983; 308: 237–41.
102.
MintonSDSteichenJJTsangRC. Bone mineral content in term and preterm appropriate for gestational age infants. J Pediatr1979; 95: 1037–42.
103.
SagyMBirenbaumEBalinA. Phosphate depiction syndrome in a premature infant fed human milk. J Pediatr1980; 96: 683–5.
104.
McIntoshNDe CurtisMWilliamsJ. Failure of mineral supplementation to reduce incidence of rickets in very low birthweight infants. Lancet1986; ii: 981–2.
105.
MariePJTraversR. Continuous infusion of 1,25 dihydroxyvitamin D, stimulates bone turnover in the normal young mouse. Calcif Tissue Int1983; 35: 418–22.
106.
RaiszLGMainaDMGworekSC. Hormonal control of bone collagen synthesis in vitro. Inhibitory effect of 1-hydroxylated Vitamin D metabolites. Endocrinol1978; 102: 731–69.
107.
WalterEGMurphyJFBrownRCWoodheadJSGrayOP. Vitamin D metabolism in rachitic pre-term infants. Lancet1983; ii: 629.
108.
MarkestadTAksnesLFinnePHAarksogD. Vitamin D nutritional status of premature infants supplemented with 500 IU Vitamin D2 per day. Acta Pediatr Scand1983; 72: 517–20.
109.
American Academy of Pediatrics Committee on Nutrition. Vitamin and mineral supplement needs in normal children in the United States. Pediatr1980; 66: 1015–21.
110.
RobinsonMJMerrettALTetlowVACompstonJE. Plasma 25-hydroxyvitamin D concentrations in preterm infants receiving oral Vitamin D supplements. Arch Dis Child1981; 56: 144–5.
111.
McIntoshNLiveseyABrookeOG. Plasma 25 hydroxy Vitamin D and rickets in infants of extremely low birthweight. Arch Dis Child1982; 57: 848–50.
112.
HillmanLSHollisBSalmonesS. Absorption, dosage and effect on mineral homeostasis of 5-hydroxy-cholecalciferol in premature infants: Comparison with 400 and 800 IU Vitamin D2 supplementation. J Pediatr1985; 106: 981–9.
113.
BrookeOG. Supplementary Vitamin D in infancy and childhood. Arch Dis Child1983; 58: 573–4.
114.
PooleRLRuppCAKernerJA. Calcium and phosphorus in neonatal parenteral nutrition solutions. J Parent Enter Nutr1983; 7: 358–60.
115.
AikenGLenneyW. Calcium and phosphate content of intravenous feeding regimens for very low birthweight infants. Arch Dis Child1986; 61: 495–501.
116.
MacMahonPBlairMETreweekePKovarIZ. Association of mineral composition of neonatal intravenous feeding solutions and metabolic bone disease of prematurity. Arch Dis Child1989; 64: 489–93.
117.
MacMahonPMaynePDBlairMPopeCKovarIZ. Calcium and phosphorus solubility in neonatal intravenous feeding solutions. Arch Dis Child1990; 65: 352–3.
118.
MacMahonPMaynePDBlairMPopeCKovarIZ. Acid-base status of the preterm infant and the formulation of intravenous feeding solutions. Arch Dis Child1990; 65: 354–6.
