Higher versus lower protein intake in formula-fed low birth weight infants
In low-birth-weight infants, protein intake of between 3.0 grams/kg/day and 4.0 grams/kg/day from formula milk accelerates weight gain, but higher protein intake can lead to increases in blood urea and nitrogen concentrations and metabolic acidosis. Data on long-term growth and neurodevelopmental outcomes related to higher protein intake are inadequate to make any policy recommendations regarding this intervention
RHL Commentary by Go M and Schelonka RL
Dietary protein provides essential amino acids necessary for normal growth and development. Sufficient energy and other nutrients are needed to allow protein to be used for tissue growth rather than as a fuel source. When energy is limited, protein is used as an energy source, and optimal protein synthesis cannot occur (1). The recommendation of an estimated protein intake of 3.5–4 grams/kg/day required for growth is based on theoretical calculations for a healthy growing fetus (2).
Exactly how much protein is required for optimal growth after birth is not known. Benefits of higher protein intake may include growth and turnover of lean tissue, building bones and blood constituents, and synthesis of hormones. Protein deficiency in infancy may cause growth failure and, when extreme, may lead to edema and lower resistance to infection. Too much protein increases blood urea, hydrogen ions, and amino acids (i.e. phenylalanine, tyrosine), resulting in metabolic acidosis. This combination of metabolic disturbances may harm the developing brain. This Cochrane review (3) sought to determine whether, in formula-fed preterm infants weighing <2500 grams, higher (≥3.0 grams/kg/day) versus lower (<3.0 grams/kg/day) protein intake during the initial hospital stay results in improved growth and neurodevelopmental outcomes without any short- and long-term morbidity.
2. METHODS OF THE REVIEW
The Cochrane review authors searched English-language databases as well as conference proceedings for related clinical trials. Only randomized controlled trials (RCTs) with LBW participants were included. Trials were included in the review if the LBW infants in the studies did not receive intravenous nutrition and were exclusively fed on formula milk. Three levels of protein intake were evaluated: low (<3 grams/kg/day), high (≥3 grams/kg/day but < 4 grams/kg/day), and very high (≥4 grams/kg/day). All trial publications identified from the complete search were assessed for relevance independently by the two review authors.
3. RESULTS OF THE REVIEW
Five studies were included in the meta-analysis with a total of 151 participants. There was significantly higher weight gain of 2.4 grams/kg/day [weighted mean difference (WMD) 2.36 g/kg/day; 95% confidence interval (CI) 1.31–3.40] and significantly higher nitrogen accretion 144 mg/kg/day (WMD 143.7 mg/kg/day, 95% CI 128.7, 158.8) in infants who had received the higher protein content formula milk (≥3 g/kg/day but <4 g/kg/day). There were no differences in the adverse outcomes of necrotizing enterocolitis, sepsis or diarrhoea. One study had assessed behaviour before 2 months of age in 15 infants, and found infants receiving the higher protein formula performed significantly better (in terms of orientation, habituation and autonomic stability clusters) than infants receiving the lower protein formula (4). None of the studies reported results of detailed neurodevelopmental testing at 18 months or later. In one study involving infants who were <1300 grams at birth and who received very high protein intake (up to 7 grams/kg/day), more children at follow-up had IQ scores <90 (5).
4.1 Applicability of the results
The available evidence suggests that by increasing protein quantity in feeds there is a modest increase in daily weight gain in LBW infants of about 3 grams/kg/day. The cumulative weight gain over the first few months of age may be clinically meaningful.
Excess of dietary protein is wasteful and may be harmful. A recent multicenter, randomized controlled trial that compared 1138 healthy formula-fed infants (randomly assigned to receive either 1.77–2.2 g protein/100 kcal or 2.9–4.4 grams protein/100 kcal) with 619 exclusively breastfed infants found that the higher protein intake from formula milk was associated with greater weight in the first 2 years of life, but it had no effect on length. The weight-for length Z-score at 24 months were similar in the lower-protein-formula-fed and the breastfed infants. Although not proven in this study, the authors expressed concern that rapid weight gain during infancy, as seen in the high protein formula fed infants, could increase the risk of childhood overweight and obesity (6).
Overall, the findings of this Cochrane review are not applicable to under-resourced settings, where feedings infants with formula milk is associated with higher costs and increase in infant mortality, which is particularly evident in the in the first months after birth (7).
4.2 Implementation of the intervention
The WHO and UNICEF Global Strategy for Infant and Youth Child Feeding (8) states that breastfeeding is an unequalled way of providing ideal food for the healthy growth and development of infants (both term and preterm) and strongly recommends exclusive breastfeeding for the first 6 months of age. Preterm infants weighing <1500 grams at birth should be given a human milk fortifier. Although protein content in human milk varies, human milk protein tends to have a higher biological value than cow's milk protein.
4.3 Implications for research
Additional studies are needed to determine optimal protein and energy intake for low-birth-weight infants. Future studies should examine long-term growth and neurodevelopmetal outcomes as well as early “metabolic programming” for chronic diseases such as diabetes and obesity. There is an important gap in the data from current studies regarding the amount of dietary protein and impact on head circumference or length measurements. This is particularly germane to outcomes since head circumference, rather than body mass, is a strong predictor of brain growth (9).
- Kashyap S, Schulze KF, Ramakrishnan R, Dell RB, Heird WC. Evaluation of a mathematical model for predicting the relationship between protein and energy intakes of low-birth-weight infants and the rate and composition of weight gain. Pediatric Research 1994;35:704-712.
- Kleinman RE, ed. Nutritional needs of preterm infants. Pediatric nutrition handbook 6th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
- Premji SS, Fenton T, Sauve RS. Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane Database of Systematic Reviews 2006;Issue 1. Art. No.: CD003959; DOI: 10.1002/14651858.CD003959.pub2.
- Bhatia J, Rassin DK, Cerreto MC, Bee DE. Effect of protein/energy ratio on growth and behavior of premature infants: preliminary findings. Journal of Pediatrics 1991;119:103-110.
- Goldman HI, Liebman OB, Freudenthal R, Reuben R. Effects of early dietary protein intake on low-birth-weight infants: evaluation at 3 years of age. Journal of Pediatrics 1971;78:126-129.
- Koletzko B, von KR, Closa R, Escribano J, Scaglioni S, Giovannini M, et al. Lower protein in infant formula is associated with lower weight up to age 2 y: a randomized clinical trial. American Journal of Clinical Nutrition 2009;89:1836-1845.
- WHO Collaborative Study Team on the Role of Breastfeeding on the Prevention of Infant Mortality. Effect of breastfeeding on infant and child mortality due to infectious diseases in less developed countries: a pooled analysis. The Lancet 2000 5;355:451-455
- WHO and UNICEF. Global Strategy for Infant and Youth Child Feeding. Geneva: World Health Organization; 2003.
- Cheong JL, Hunt RW, Anderson PJ, Howard K, Thompson DK, Wang HX, et al. Head growth in preterm infants: correlation with magnetic resonance imaging and neurodevelopmental outcome. Pediatrics 2008;121:e1534-e1540.
This document should be cited as: Go M, Schelonka RL. Higher versus lower protein intake in formula-fed low birth weight infants: RHL commentary (last revised: 1 July 2010). The WHO Reproductive Health Library; Geneva: World Health Organization.