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

Review question

Does feeding preterm or low birth weight infants (< 2.5 kilograms) higher protein intake during the initial hospital stay improve growth and developmental outcomes?


Infants grow quickly and need more protein for each kilogram of body weight than older children and adults. Infants born with low birth weight, for example, those who are born prematurely, need more protein because of their fast growth rates.

Study characteristics

We identified six eligible trials that enrolled a total of 218 infants through searches updated to August 2, 2019.

Key results

Higher protein intake (3 to 4 versus less than 3 grams of protein per kilogram) resulted in slightly greater weight gain, of around 2 grams per kilogram per day. We are uncertain whether this difference in protein intake affects head and length growth because not many infants were studied. Existing research does support specific recommendations regarding formula with protein content that provides more than 4 g/kg/d. No harmful effects were observed.

Certainty of evidence

The review was limited in the conclusions made because differences in protein content among comparison groups in some individual trials were small and formulas differed substantially across studies; some studies included healthier and more mature preterm infants. Information on long-term outcomes is limited.

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 neurodevelopment. Research is needed to investigate the safety and effectiveness of protein intake ≥ 4.0 g/kg/d.

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 leading to 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- or long-term morbidity.

Specific objectives were to examine the following comparisons of interventions and to conduct subgroup analyses if possible.

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.

Search strategy: 

We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), in the Cochrane Library (August 2, 2019); OVID MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, and Ovid MEDLINE(R) (to August 2, 2019); MEDLINE via PubMed (to August 2, 2019) for the previous year; and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (to August 2, 2019). We also searched clinical trials databases and the reference lists of retrieved articles for randomized controlled trials (RCTs) and quasi-randomized trials.

Selection criteria: 

We included RCTs 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. We excluded studies if infants received partial parenteral nutrition during the study period, or if infants were fed formula as a supplement to human milk.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane and the GRADE approach to assess the certainty of evidence.

Main results: 

We identified six eligible trials that enrolled 218 infants through searches updated to August 2, 2019. Five studies compared low (< 3 g/kg/d) versus high (3.0 to 4.0 g/kg/d) protein intake using formulas that kept other nutrients constant. The trials were small (n = 139), and almost all had methodological limitations; the most frequent uncertainty was about attrition. Low-certainty evidence suggests improved weight gain (mean difference [MD] 2.36 g/kg/d, 95% confidence interval [CI] 1.31 to 3.40) and higher nitrogen accretion in infants receiving formula with higher protein content (3.0 to 4.0 g/kg/d) versus lower protein content (< 3 g/kg/d), while other nutrients were kept constant. No significant differences were seen in rates of necrotizing enterocolitis, sepsis, or diarrhea. We are uncertain whether high versus low protein intake affects head growth (MD 0.37 cm/week, 95% CI 0.16 to 0.58; n = 18) and length gain (MD 0.16 cm/week, 95% CI -0.02 to 0.34; n = 48), but sample sizes were small for these comparisons.

One study compared high (3.0 to 4.0 g/kg/d) versus very high (≥ 4 g/kg/d) protein intake (average intakes were 3.6 and 4.1 g/kg/d) during and after an initial hospital stay (n = 77). Moderate-certainty evidence shows no significant differences in weight gain or length gain to discharge, term, and 12 weeks corrected age from very high protein intake (4.1 versus 3.6 g/kg/d). Three of the 24 infants receiving very high protein intake developed uremia.