Background - Methods - Results - References
The role of human milk for enteral feeding of preterm infants is less well defined. Preterm human milk provides insufficient quantities of protein, sodium, calcium and phosphorus to meet the estimated needs of these infants. In addition, large fluid volumes may be required to provide sufficient calories to maintain adequate growth.
Two-thirds of the fetal body mineral content is acquired in the third trimester of pregnancy (Itani 1991). Preterm infants therefore are born with low skeletal stores of calcium and phosphorus, and have very high requirements for these minerals if they are to attain adequate postnatal skeletal growth. These requirements may not be met by feeding human milk alone. Observational studies have shown that preterm infants fed human milk alone may have hypophosphatemia (Atkinson 1983), radiologic evidence of poor bone mineralization (Rowe 1979, Atkinson 1983), and elevated alkaline phosphatase activity (Rowe 1984), and this may be associated with fractures and lower-than-expected growth rates.
In contrast, provision of supplemental calcium and phosphorus may have adverse effects including hypercalcemia, nephrocalcinosis and feeding intolerance.
For a detailed discussion of the suitability of human milk for low-birthweight infants, see Schanler 1995.
2. Secondary outcomes
a. Bone metabolism
Incidence of fractures
b. Adverse effects
Significant hypercalcemia (>3mmol/l)
Nephrocalcinosis
Impaired renal function
Feed intolerance
The MEDLINE search included the search terms "Milk,-Human", "Infant,-Newborn", and "Calcium" or "Phosphorus,-Dietary", including all subheadings for each term.
Additional information was requested from the authors of each trial to clarify methodology and results as necessary.
Each author extracted the data separately, compared data, and resolved differences.
The standard method of the Cochrane NRG was used to synthesize the data.
Excluded studies are listed in the table "Characteristics of Excluded Studies". Atkinson 1989 measured growth outcomes but unfortunately the data were lost (personal communication - Dr S.Atkinson). Sann 1985 did not report any of the pre-specified clinical outcomes and evaluated urinary excretion of calcium and phosphorus as a proxy for mineral accretion and therefore bone mineralization. Salle 1986 similarly did not report any clinical outcomes and reported only urinary and fecal calcium and phosphorus excretion, as well as fecal fat excretion. Gupta provided unpublished data from a randomized trial of calcium supplementation alone and calcium and phosphorus supplementation of human milk. There are concerns about the methodological quality of this study as some included infants did not have randomization applied for "ethical reasons" and there were important disparities in the demographic characteristics between the control and treatment groups. Gross 1987, Greer 1988 and Lucas 1996 evaluated mineral supplementation in the context of multicomponent fortifier or preterm formula and are discussed in the review on multicomponent fortification of human milk (Kuschel 1998). Neither Schanler 1988 nor Senterre 1983 randomized infants in their studies. Hall 1993 randomized infants to receive supplementation at discharge. Faerk 2000 randomized infants to supplementation with phosphorus, multicomponent fortifier, or preterm formula and did not have a control group without supplementation. However, in the publication, post-hoc analysis of infants who did not receive any supplementation of their mothers' own milk was performed.
Case reports of significant metabolic bone disease in very low birth weight infants fed unsupplemented human milk, along with the discrepancy between the content of human milk and the known accretion rates of calcium and phosphorus in-utero, have led to widespread mineral supplementation of human milk and preterm formulae in clinical practice. A recent systematic review of the effect of fortification of human milk with multicomponent fortifiers containing supplemental minerals failed to demonstrate any significant change in alkaline phosphatase levels at study completion (Kuschel 1998). The meta-analysis of fortification in that review suggested that bone mineral content was increased, but this may be biased because of the exclusion of data from some studies which reported no difference.
| Study | Reason for exclusion |
| Atkinson 1989 | Published in abstract form only, with no clinical results available (data lost). |
| Faerk 2000 | No randomization to unsupplemented control group. |
| Greer 1988 | Supplementation with calcium, phosphate and protein. This study is included in the review on multicomponent fortification (Kuschel 1998). |
| Gross 1987 | Mineral supplementation was in the form of multicomponent fortifier or premature formula. This study is included in the multicomponent fortification review. |
| Gupta | Comparison of unsupplemented human milk versus human milk supplemented with calcium and with calcium and phosphorus. There are concerns about the randomization process and disparity between control and treatment groups. |
| Hall 1993 | Intervention performed on preterm infants at discharge from hospital. |
| Lucas 1996 | Supplementation of human milk with a multicomponent fortifier vs. supplementation with phosphate alone. This study is included in the review on multicomponent fortification (Kuschel 1998). |
| Salle 1986 | No pre-specified clinical outcomes. All outcomes biochemical. |
| Sann 1985 | No pre-specified clinical outcomes. Outcomes biochemical (urinary calcium and phosphate losses). |
| Schanler 1988 | Not randomized. |
| Senterre 1983 | Not randomized. |
Atkinson SA, Whyte RK, Fraser D, Stanhope R. A randomized trial of calcium and phosphorus supplements in low birthweight infants fed mother's milk. Proc Can Fed Biol Sci 1989;32:Abstr.
Faerk 2000 {published data only}
Faerk J, Petersen S, Peitersen B, Michaelsen KF. Diet and bone mineral content at term in premature infants. Pediatr Res 2000;47:148-156.
Greer 1988 {published and unpublished data}
Greer FR, McCormick A. Improved bone mineralization and growth in premature infants fed fortified own mother's milk. J Pediatr 1988;112:961-969.
Gross 1987 {published data only}
Gross SJ. Bone mineralization in preterm infants fed human milk with and without mineral supplementation. J Pediatr 1987;111:450-458.
Gupta G. Unpublished data.
Hall 1993 {published data only}
Hall RT, Wheeler RE, Rippetoe LE. Calcium and phosphorus supplementation after initial hospital discharge in breast-fed infants of less than 1800 grams birth weight. J Perinatol 1993;13:272-278.
Lucas 1996 {published and unpublished data}
Lucas A, Fewtrell MS, Morley R, et al. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am J Clin Nutr 1996;64:142-151.
Salle 1986 {published data only}
Salle B, Senterre J, Putet G, Rigo J. Effects of calcium and phosphorus supplementation on calcium retention and fat absorption in preterm infants fed pooled human milk. J Pediatr Gastroenterol Nutr 1986;5:638-642.
Sann 1985 {published data only}
Sann L, Loras B, David L, Durr F, Simonnet C, Baltassat P, Bethenod M. Effect of phosphorus supplementation to breast fed very low birthweight infants on urinary calcium excretion, serum immunoreactive parathyroid hormone and plasma 1,25-dihydroxy-vitamin D concentration. Acta Paediatr Scand 1985;74:664-668.
Schanler 1988 {published data only}
Schanler RJ, Garza C. Improved mineral balance in very low birth weight infants fed fortified human milk. J Pediatr 1988;112:452-456.
Senterre 1983 {published data only}
Senterre J, Putet G, Salle B, Rigo J. Effects of vitamin D and phosphorus supplementation on calcium retention in preterm infants fed banked human milk. J Pediatr 1983;103:305-307.
* Boehm G, Kirchner B. Calcium and phosphorus homeostasis in very-low-birth-weight infants appropriate for gestational age fed human milk. Biomed Biochim Acta 1988;47:529-536.
* indicates the primary reference for the study
Atkinson SA, Radde IC, Anderson GH. Macromineral balances in premature infants fed their own mothers' milk or formula. J Pediatr 1983;102:99-106.
Itani O, Tsang RC. Calcium, phosphorus, and magnesium in the newborn: pathophysiology and management. In: Hay WW Jr, editor(s). Neonatal Nutrition and Metabolism. St. Louis: Mosby-Year Book, Inc:171-202.
Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants (Cochrane Review). In: The Cochrane Library, Issue Issue 4, 1998. Oxford: Update Software.
Rowe JC, Wood DH, Rowe DW, Raisz LG. Nutritional hypophosphatemic rickets in a premature infant fed breast milk. New Engl J Med 1979;300:293-296.
Rowe J, Rowe D, Horak E, et al. Hypophosphatemia and hypercalciuria in small premature infants fed human milk: evidence for inadequate dietary phosphorus. J Pediatr 1984;104:112-117.
Schanler RJ. Suitability of human milk for the low-birthweight infant. Clin Perinatol 1995;22:207-222.