Hydrolyzed Doesn’t Always Mean Better: Rethinking Protein for Premature Infants

If a formula is easier to digest, shouldn’t it automatically be better for a premature infant?

Working as a diet technician in the Infant Nutrition Division at Golisano Children’s Hospital, I have seen how important nutrition is for premature infants. Our team prepares and delivers breast milk and specialized formulas for infants who may receive nutrition through feeding tubes, parenteral nutrition, or breast or bottle feeding. In the NICU, nutrition is complex and a critical component of medical treatment and development.

Because premature infants have immature digestive systems and high nutritional needs, feeding decisions are made carefully and continually reassessed. One option used in some situations is hydrolyzed protein formula. But does breaking protein into smaller pieces automatically make it safer or better for every premature infant?

 

What does “hydrolyzed” actually mean?

Hydrolyzed formulas contain proteins that have been broken down into smaller peptides, which, in theory, makes them easier to digest and may improve feeding tolerance. This could be beneficial, particularly for infants whose digestive systems are still developing. However, easier digestion does not necessarily mean improved growth, nutrient absorption, or reduced risk of complications such as necrotizing enterocolitis (NEC).

Hydrolyzed formulas are sometimes selected because they are perceived to improve feeding tolerance. This belief is understandable, but the available evidence is not as conclusive as the label “hydrolyzed” might suggest.

 

What does the evidence show?

A 2022 systematic review and meta-analysis by Li et al. examined 10 studies involving 886 preterm infants. The researchers found that hydrolyzed formulas were associated with a lower rate of feeding intolerance and a shorter time to reach full enteral feeding. However, there was no statistically significant reduction in NEC. The confidence interval included the possibility of no benefit, meaning the results were not strong enough to establish whether hydrolyzed formulas prevent this complication (Li et al., 2022).

Other researchers present a more cautious perspective. A 2019 Cochrane review analyzed 11 trials involving 665 infants and found no strong or consistent evidence that hydrolyzed formulas improved digestion or changed the risk of severe bowel problems. The authors also noted that many of the studies were small and had methodological limitations (Ng et al., 2019).

Individual clinical trials further demonstrate why the evidence remains mixed. In a randomized controlled trial of 60 preterm infants, Baldassarre et al. (2019) found no differences in measures of feeding tolerance between infants receiving intact-protein and extensively hydrolyzed formulas. In a smaller subset of infants who received at least 75% of their enteral intake from the study formula, the intact-protein group reached full enteral feeding sooner, with a median of 10 days compared with 14 days in the hydrolyzed group. No cases of NEC occurred in either group. Although this was a small study, it provides another example of why hydrolyzed protein does not consistently produce better feeding outcomes.

The current professional guidance is more nuanced than simply labeling hydrolyzed formula as better or worse. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper reports that hydrolyzed protein can accelerate gastrointestinal transit and enteral feeding advancement in preterm infants. However, there are no data showing that routine use improves long-term outcomes. ESPGHAN states that hydrolyzed protein may be used for early enteral feeding when human milk is unavailable, rather than recommending it as the standard choice for every formula-fed preterm infant (Embleton et al., 2023). With updated professional guidance on enteral nutrition in preterm infants and continued use of hydrolyzed formulas in neonatal care, understanding what these formulas can and cannot accomplish is important for setting health and growth goals.

There are also potential nutritional disadvantages to consider. Hydrolysis alters amino acid kinetics and may reduce nutrient utilization, particularly nitrogen. Some studies have reported slower weight gain and lower nutritional efficiency with hydrolyzed formulas, although increasing protein concentration can help compensate for reduced protein retention. Hydrolyzed formulas can also have increased osmolality (Verduci et al., 2021; Embleton et al., 2023).

Another challenge is that “hydrolyzed formula” is not one standardized product. Formulas can be partially or extensively hydrolyzed, and commercial formulas differ in the size of their remaining protein peptides. These differences may produce different functional effects, meaning results from one hydrolyzed formula cannot necessarily be applied to every hydrolyzed formula used in the NICU (Embleton et al., 2023).

 

Why does this matter in the NICU?

In my experience working in the NICU, hydrolyzed formulas are not chosen simply because they are considered better. They are used in specific clinical situations, and the infant’s tolerance, growth, medical condition, overall feeding plan, and growth goals are all factors that dietitians and providers must consider. Witnessing these decisions and preparing so many hydrolyzed formulas brought my attention to this very niche debate and made me realize how complex nutritional strategies are in pediatrics and neonatology.

In the NICU, no two infants have exactly the same medical needs. A premature infant’s nutritional plan may depend on gestational age, weight, medical conditions, tolerance, growth, and whether the infant is receiving breast milk, fortification, or formula.

This is why I believe hydrolyzed protein should not be viewed as automatically superior. It may be a useful option for certain infants, but the choice of formula should rest on more than the assumption that smaller protein molecules will solve feeding problems.

For parents and families, the most important step is to ask questions: Why was a specific formula selected? Is the goal to improve feeding tolerance, support growth, address an allergy, or manage another medical concern? What outcomes will the healthcare team monitor and report?

Nutritional decisions should be an ongoing conversation based on the infant’s individual needs and the best available evidence, not simply on the idea that a product with more specialized processing will produce better outcomes.

Premature infants deserve nutrition plans that are carefully considered and individualized. Hydrolyzed protein may benefit some infants, but “easier to digest” should not necessarily be interpreted as “better feeding outcomes.”

 

By Allison L. Kimmerer, A Master's of Medical Science student at the University of Kentucky

 

References

Baldassarre, M. E., Di Mauro, A., Fanelli, M., Capozza, M., Wampler, J. L., Cooper, T., & Laforgia, N. (2019). Shorter time to full preterm feeding using intact protein formula: A randomized controlled trial. International Journal of Environmental Research and Public Health, 16(16), 2911. https://doi.org/10.3390/ijerph16162911

Embleton, N. D., Moltu, S. J., Lapillonne, A., van den Akker, C. H. P., Carnielli, V., Fusch, C., Gerasimidis, K., van Goudoever, J. B., Haiden, N., Iacobelli, S., Johnson, M. J., Meyer, S., Mihatsch, W., Saenz de Pipaon, M., Rigo, J., Zachariassen, G., Bronsky, J., Indrio, F., Köglmeier, J., ... Domellöf, M. (2023). Enteral nutrition in preterm infants (2022): A position paper from the ESPGHAN Committee on Nutrition and invited experts. Journal of Pediatric Gastroenterology and Nutrition, 76(2), 248–268. https://doi.org/10.1097/MPG.0000000000003642

Li, M., Fang, Y., Lian, Y., Lu, X., Qiu, M., & He, Y. (2022). Effect of hydrolyzed formulas on gastrointestinal tolerance in preterm infants: A systematic review and meta-analysis. The Journal of Maternal-Fetal & Neonatal Medicine, 35(25), 10173–10180. https://doi.org/10.1080/14767058.2022.2122794

Ng, D. H. C., Klassen, J. R. L., Embleton, N. D., & McGuire, W. (2019). Protein hydrolysate versus standard formula for preterm infants. Cochrane Database of Systematic Reviews, 2019(7), Article CD012412. https://doi.org/10.1002/14651858.CD012412.pub3

Verduci, E., Salvatore, S., Bresesti, I., Di Profio, E., Pendezza, E., Bosetti, A., Agosti, M., Zuccotti, G. V., & D’Auria, E. (2021). Semi-elemental and elemental formulas for enteral nutrition in infants and children with medical complexity—Thinking about cow’s milk allergy and beyond. Nutrients, 13(12), 4230. https://doi.org/10.3390/nu13124230