Higher versus lower protein intake in formula-fed low birth weight infants

Dietary protein is needed for normal growth and development. The protein intake required for growth of the low birth weight infant has been estimated by the growth rate of the fetus to be 3.5 to 4.0 g/kg/d. Controlling the amount of protein given to low birth weight babies (less than 2.5 kg) fed with formula is important. Too much protein can raise blood urea and amino acid (phenylalanine) levels, and this may harm neurodevelopment. Too low protein intake may limit the growth of these infants. The review authors searched the medical literature to identify studies that compared protein intake as follows: between 3 and 4 g of protein per kg of infant body weight each day versus less than 3.0 g/kg/d or greater than 4.0 g/kg/d by low birth weight infants fed formula during their initial hospital stay. Increased protein intake resulted in greater weight gain of around 2.0 g/kg/d. Based on increased body incorporation of nitrogen, this was associated with increased lean body mass. The present conclusion was based on six studies that changed only the protein content of the formula and was supported by three additional studies that made changes in other nutrients as well. No significant difference in the concentration of plasma phenylalanine was noted between infants fed high or low protein content formula. The review was limited in the conclusions made because differences in protein content among comparison groups in some of the individual trials were small and formulas differed substantially across studies; some studies included healthier and more mature premature infants. Study periods varied from eight days to two years, so information on long-term outcomes was limited. Existing research is not adequate to allow specific recommendations regarding formula with protein content that provides more than 4.0 g/kg/d.

Authors' conclusions: 

Higher protein intake (≥ 3.0 g/kg/d but < 4.0 g/kg/d) from formula accelerates weight gain. However, limited information is available regarding the impact of higher formula protein intake on long-term outcomes such as neurodevelopmental abnormalities. Available evidence is not adequate to permit specific recommendations regarding the provision of very high protein intake (> 4.0 g/kg/d) from formula during the initial hospital stay or after discharge.

Read the full abstract...

The ideal quantity of dietary protein for formula-fed low birth weight infants is still a matter of debate. Protein intake must be sufficient to achieve normal growth without negative effects such as acidosis, uremia, and elevated levels of circulating amino acids.


To determine whether higher (≥ 3.0 g/kg/d) versus lower (< 3.0 g/kg/d) protein intake during the initial hospital stay of formula-fed preterm infants or low birth weight infants (< 2.5 kilograms) results in improved growth and neurodevelopmental outcomes without evidence of short- and long-term morbidity.

To examine the following distinctions in protein intake.

1. Low protein intake if the amount was less than 3.0 g/kg/d.

2. High protein intake if the amount was equal to or greater than 3.0 g/kg/d but less than 4.0 g/kg/d.

3. Very high protein intake if the amount was equal to or greater than 4.0 g/kg/d.

If the reviewed studies combined alterations of protein and energy, subgroup analyses were to be carried out for the planned categories of protein intake according to the following predefined energy intake categories.

1. Low energy intake: less than 105 kcal/kg/d.

2. Medium energy intake: greater than or equal to 105 kcal/kg/d and less than or equal to 135 kcal/kg/d.

3. High energy intake: greater than 135 kcal/kg/d.

As the Ziegler-Fomon reference fetus estimates different protein requirements for infants based on birth weight, subgroup analyses were to be undertaken for the following birth weight categories.

1. < 800 grams.

2. 800 to 1199 grams.

3. 1200 to 1799 grams.

4. 1800 to 2499 grams.

Search strategy: 

The standard search methods of the Cochrane Neonatal Review Group were used. MEDLINE, CINAHL, PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library) were searched.

Selection criteria: 

Randomized controlled trials contrasting levels of formula protein intake as low (< 3.0 g/kg/d), high (≥ 3.0 g/kg/d but < 4.0 g/kg/d), or very high (≥ 4.0 g/kg/d) in formula-fed hospitalized neonates weighing less than 2.5 kilograms were included. Studies were excluded if infants received partial parenteral nutrition during the study period or were fed formula as a supplement to human milk. Studies in which nutrients other than protein also varied were added in a post-facto analysis.

Data collection and analysis: 

The standard methods of the Cochrane Neonatal Review Group were used.

Main results: 

Five studies compared low versus high protein intake. Improved weight gain and higher nitrogen accretion were demonstrated in infants receiving formula with higher protein content while other nutrients were kept constant. No significant differences were seen in rates of necrotizing enterocolitis, sepsis, or diarrhea.

One study compared high versus very high protein intake during and after an initial hospital stay. Very high protein intake promoted improved gain in length at term, but differences did not remain significant at 12 weeks corrected age. Three of the 24 infants receiving very high protein intake developed uremia.

A post-facto analysis revealed further improvement in all growth parameters in infants receiving formula with higher protein content. No significant difference in the concentration of plasma phenylalanine was noted between high and low protein intake groups. However, one study (Goldman 1969) documented a significantly increased incidence of low intelligence quotient (IQ) scores among infants of birth weight less than 1300 grams who received a very high protein intake (6 to 7.2 g/kg).