Review question
Does feeding preterm infants with nutrient-enriched formula (extra energy and protein) compared with standard formula increase the rate of growth and improve development?
Background
Standard formula (designed for term infants) may not provide preterm infants with sufficient quantities of nutrients to support optimal growth and development. Nutrient-enriched formula (containing extra protein and energy from carbohydrates or fat and other nutrients) has about 20% higher nutrient content than standard formula. Feeding preterm infants, particularly very preterm infants, with nutrient-enriched formula might increase nutrient intake and growth rates, and might improve development.
Study characteristics
We found seven trials; most were small (involving 590 infants in total), and some were prone to bias.
Key results
Nutrient-enriched versus standard formula for preterm infants does not reduce the time taken to regain birth weight but is associated with higher rates of weight gain and head growth (although not length gain) during neonatal unit stay after birth. Only limited data are available for growth and developmental outcomes assessed beyond infancy, and these do not show consistent effects. No evidence suggests other potential benefits or harms of nutrient-enriched formulas, including effects on feeding or bowel problems.
Conclusions
Although available trial data show that nutrient-enriched formulas increase growth rates of preterm infants during their initial hospital admission, they do not provide evidence of effects on longer-term growth or development. Further randomised trials would be needed to resolve this uncertainty.
Available trial data show that feeding preterm infants nutrient-enriched (compared with standard) formulas has only modest effects on growth rates during their initial hospital admission. No evidence suggests effects on long-term growth or development. The GRADE assessment indicates that the certainty of this evidence is low, and that these findings should be interpreted and applied with caution. Further randomised trials would be needed to resolve this uncertainty.
Preterm infants may accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with nutrient-enriched rather than standard formula might increase nutrient accretion and growth rates and might improve neurodevelopmental outcomes.
To compare the effects of feeding with nutrient-enriched formula versus standard formula on growth and development of preterm infants.
We used the Cochrane Neonatal standard search strategy. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11), MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (until November 2018), as well as conference proceedings, previous reviews, and clinical trials databases.
Randomised and quasi-randomised controlled trials that compared feeding preterm infants with nutrient-enriched formula (protein and energy plus minerals, vitamins, or other nutrients) versus standard formula.
We extracted data using the Cochrane Neonatal standard methods. Two review authors separately evaluated trial quality and extracted and synthesised data using risk ratios (RRs), risk differences, and mean differences (MDs). We assessed certainty of evidence at the outcome level using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods.
We identified seven trials in which a total of 590 preterm infants participated. Most participants were clinically stable preterm infants of birth weight less than 1850 g. Few participants were extremely preterm, extremely low birth weight, or growth restricted at birth. Trials were conducted more than 30 years ago, were formula industry funded, and were small with methodological weaknesses (including lack of masking) that might bias effect estimates. Meta-analyses of in-hospital growth parameters were limited by statistical heterogeneity. There is no evidence of an effect on time to regain birth weight (MD -1.48 days, 95% confidence interval (CI) -4.73 to 1.77) and low-certainty evidence suggests that feeding with nutrient-enriched formula increases in-hospital rates of weight gain (MD 2.43 g/kg/d, 95% CI 1.60 to 3.26) and head circumference growth (MD 1.04 mm/week, 95% CI 0.18 to 1.89). Meta-analysis did not show an effect on the average rate of length gain (MD 0.22 mm/week, 95% CI -0.70 to 1.13). Fewer data are available for growth and developmental outcomes assessed beyond infancy, and these do not show consistent effects of nutrient-enriched formula feeding. Data from two trials did not show an effect on Bayley Mental Development Index scores at 18 months post term (MD 2.87, 95% CI -1.38 to 7.12; moderate-certainty evidence). Infants who received nutrient-enriched formula had higher Bayley Psychomotor Development Index scores at 18 months post term (MD 6.56. 95% CI 2.87 to 10.26; low-certainty evidence), but no evidence suggested an effect on cerebral palsy (typical RR 0.79, 95% CI 0.30 to 2.07; 2 studies, 377 infants). Available data did not indicate any other benefits or harms and provided low-certainty evidence about the effect of nutrient-enriched formula feeding on the risk of necrotising enterocolitis in preterm infants (typical RR 0.72, 95% CI 0.41 to 1.25; 3 studies, 489 infants).