See “One Extra Gram of Protein to Preterm Infants From Birth to 1800 g: A Single-Blinded Randomized Clinical Trial” by Bellagamba et al on page 879 and See “Intakes of Micronutrients Are Associated With Early Growth in Extremely Preterm Infants” by Sjöström et al on page 885.
In the present issue of the Journal of Pediatric Gastroenterology and Nutrition, Bellagamba et al (1) describe the effect of an additional gram of amino acids or protein during both the parenteral and enteral nutritional management from birth to a weight of 1800 g. In total the difference was 0.8 g · kg−1 · day−1 (3.3 versus 4.1 g · kg−1 · day−1). The randomized study revealed no significant outcomes with regard to short-term or long-term growth in a relatively large group of 164 infants, neither did the study group find any differences in neurocognitive scores at an corrected age of 2 years.
This is an important study as hardly any nutritional intervention studies have been published that are large enough to draw any conclusions with regard to neurocognitive outcomes. A follow-up rate of >90% at a corrected postconceptional age of 2 years allows also firm conclusions. So one could easily agree with the authors that providing preterm infants with a combined enteral and parenteral amino acid intake above 3.3 g · kg−1 · day−1 during neonatal hospitalization does not have much use.
But is that statement true? There are several issues to consider. First, as can be deduced from the present article, amino acids/protein do not seem to be the limiting macronutrient in this center, although deficits in growth clearly occur. Recently, hypophosphatemia has been recognized as complication during high amino acid intakes, resulting in increased morbity (2), and highlighting the importance of micronutrients. In the express study (3) found that the intakes of several micronutrients independently affected the growth. Furthermore, protein energy ratio is important as well, as was shown elegantly by a series of articles by Kashyap et al (4). These studies indicate that a preterm infant needs “enough” energy to use the additional protein for protein synthesis. Using stable isotopes, we found a significant effect of adding energy through iv lipids on albumin synthesis as well (5).
Second, even short interventions may have long-lasting results. A typical example is the fraction of inspired oxygen used during resuscitation after birth, which clearly affects outcomes (6). Many nutritional intervention studies have shown beneficial effects in the first few days to weeks. Increasing protein intakes resulted in higher head circumference growth rates (7,8), higher nitrogen balances (9), protein synthesis rates, and improved antioxidant defense mechanisms (10). In a similar-sized study following birth, boys had a normal outcome significantly more often if amino acids were administered from birth onward and following adjustment for confounders. Interestingly, the mental developmental index was lower in the small number of girls who survived without major disabilities following the early administration of amino acids (11). This may be a coincidental finding as the test performed at a corrected age of 2 years may be too crude to detect subtle changes.
Third, the quality of the administered amino acid solutions and proteins may be a topic of discussion. We have hardly any clue of the requirements of individual amino acids. Protein synthesis rates are determined by the first limiting amino acid if all other factors important for growth are available appropriately.
As clinicians, we use the amino acid solution provided by the pharmacy. These solutions are not composed using actual amino acid requirement studies in either parenterally or enterally fed preterm infants. Those studies are also limited, resulting in a large trial and error method to determine the total amounts of proteins needed for optimal growth. It may well be that we provide the infants in our neonatal intensive care units with too much amino acids and proteins, just because we have not yet determined their actual individual amino acid needs.
So in conclusion, the study by Bellagamba provides relevant data, indicating that just increasing amino acid or protein intakes is not resulting in any better outcome. The control group clearly receives adequate amounts of amino acids/proteins in the setting they are taking care of. Routinely increasing amino acid intakes beyond 2.5 g · kg−1 · day−1 (parenterally) or 3.6 g · kg−1 · day−1 (enterally) is not evidence based. The other important lesson from this study is that follow-up beyond the neonatal phase is essential and should be part of each nutritional intervention trial, while being adequately powered. Only then we will get important answers to the question whether we are still under nourishing our patients. What remains are the questions whether other factors such as micronutrient status, energy protein ratio and quality of proteins administered are to be improved.
1. Bellagamba MP, Carmenati E, D’Ascenzo R, et al One extra gram of protein to preterm infants from birth to 1800 g: a single-blinded randomized clinical trial. J Pediatr Gastroenterol Nutr
2. Moltu SJ, Str⊘mmen K, Blakstad EW, et al Enhanced feeding in very-low-birth-weight infants may cause electrolyte disturbances and septicemia—a randomized, controlled trial. Clin Nutr
3. Sjöström ES, Öhlund I, Ahlsson F, Domellöf M. Intakes of micronutrients are associated with early growth in extremely preterm infants. J Pediatr Gastroenterol Nutr
4. Kashyap S, Schulze KF, Forsyth M, et al Growth, nutrient retention, and metabolic response in low birth weight infants fed varying intakes of protein and energy. J Pediatr
5. Vlaardingerbroek H, Schierbeek H, Rook D, et al Albumin synthesis in very low birth weight infants is enhanced by early parenteral lipid and high-dose amino acid administration. Clin Nutr
2015; S0261-5614: 00129-6.
6. Saugstad OD, Aune D, Aguar M, et al Systematic review and meta-analysis of optimal initial fraction of oxygen levels in the delivery room at </=32 weeks. Acta Paediatr
7. Morgan C, McGowan P, Herwitker S, et al Postnatal head growth in preterm infants: a randomized controlled parenteral nutrition study. Pediatrics
8. Moltu SJ, Blakstad EW, Str⊘mmen K, et al Enhanced feeding and diminished postnatal growth failure in very-low-birth-weight infants. J Pediatr Gastroenterol Nutr
9. Embleton ND. Optimal protein and energy intakes in preterm infants. Early Hum Dev
10. Te Braake FW, Schierbeek H, de Groof K, et al Glutathione synthesis rates after amino acid administration directly after birth in preterm infants. Am J Clin Nutr
11. van den Akker CH, te Braake FW, Weisglas-Kuperus N, et al Observational outcome results following a randomized controlled trial of early amino acid administration in preterm infants. J Pediatr Gastroenterol Nutr