Relevance. Refeeding syndrome (RFS) is a serious metabolic complication that occurs upon refeeding after a period of starvation or severe nutritional deprivation. Although this phenomenon has been well studied in adults, timely recognition, diagnostic criteria, and prevention of RFS in newborns—particularly preterm infants, those with low birth weight, and infants with fetal growth restriction—remain insufficiently standardized. A key challenge is the lack of unified diagnostic criteria for neonatal RFS, which hampers timely detection, preventive measures, and cross-study comparability.
Aim. To summarize current evidence on diagnostic criteria for RFS in neonatal practice, identify principal risk markers of its development, and propose practical approaches for clinical use.
Relevance. Refeeding syndrome (RFS) is a serious metabolic complication that occurs upon refeeding after a period of starvation or severe nutritional deprivation. Although this phenomenon has been well studied in adults, timely recognition, diagnostic criteria, and prevention of RFS in newborns—particularly preterm infants, those with low birth weight, and infants with fetal growth restriction—remain insufficiently standardized. A key challenge is the lack of unified diagnostic criteria for neonatal RFS, which hampers timely detection, preventive measures, and cross-study comparability.
Aim. To summarize current evidence on diagnostic criteria for RFS in neonatal practice, identify principal risk markers of its development, and propose practical approaches for clinical use.
Pathophysiological mechanisms. The pathophysiological mechanisms underlying RFS in newborns indicate that in states of malnutrition or intrauterine growth retardation (SGA, "small for gestational age"), there is a decrease in phosphate, potassium, magnesium, and thiamine reserves [1,2]. The reintroduction of nutritional support stimulates insulin secretion, which in turn drives an intracellular shift of glucose, phosphorus, potassium, and magnesium. This activates anabolic processes such as the synthesis of glycogen, protein, and lipids. As a result, a risk of severe electrolyte disturbances emerges.
Clinical manifestations. Clinical manifestations of neonatal RFS include hypophosphatemia, hypokalemia, hypomagnesemia, respiratory distress (due to impaired respiratory muscle function), an increased risk of intraventricular hemorrhage, and, in severe cases, death.
High-Risk Groups. Newborns at high risk of developing RFS include premature infants (< 32 weeks of gestation), those with very low birth weight (< 1500 g), infants with intrauterine growth retardation (IUGR) or who are small for gestational age, and those who have been without adequate nutritional support for a prolonged period. According to various studies, the incidence of hypophosphatemia during the refeeding period in neonates ranges from 20% to 90% [3], which highlights the significant variability in the presentation of RS.
Guideline reference. The American Society for Parenteral and Enteral Nutrition (ASPEN) defines criteria related to the risk and diagnosis of RFS (across pediatric and adult populations), including a rapid increase in energy delivery and a decrease in serum phosphate, potassium, or magnesium by ≥10% within the first 5 days of feeding [5].
Proposed provisional diagnostic criteria for neonatal RFS (based on the literature):
• serum phosphate <0.69 mmol/L (≈<2.1 mg/dL) as a marker of severe hypophosphatemia [5];
• serum potassium <3.0 mmol/L and/or magnesium <0.70 mmol/L as additional laboratory indicators [5];
• a ≥20% decrease in any of these electrolytes during the first 10 days of nutrition in the context of increasing energy delivery (enteral or parenteral).
Risk assessment and clinical context. Risk stratification should account for the pace of protein and energy escalation, the calcium-to-phosphorus ratio in solutions (specify units; often targeted near 1:1 on a molar basis), and possible thiamine deficiency [2,4].
Clinical triggers. In practice, it is useful to consider “clinical triggers” of RFS, such as the following constellation: an SGA neonate at initiation of enteral or parenteral feeding, a decline in serum phosphate within 72 hours, and subsequent clinical deterioration (increasing ventilatory support needs, intraventricular hemorrhage, metabolic instability).
Conclusions. Standardizing and implementing diagnostic criteria for RFS in neonatal practice are critical to improving the safety of nutritional support in vulnerable newborns. Systematic monitoring of electrolytes (phosphate, potassium, magnesium) and gradual escalation of energy delivery can reduce complications and improve outcomes in preterm and low-birth-weight infants.
Literature
1. Bradford C. V., Cober M., Miller J. L. Refeeding Syndrome in the Neonatal Intensive Care Unit. Journal of Pediatric Pharmacology and Therapeutics. 2021. Vol. 26, No. 8. P. 771–782. DOI: 10.5863/1551-6776-26.8.771 URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC8591996/
2. Cormack B. E., Jiang Y., Harding J. E., Crowther C. A., Bloomfield F. H.; ProVIDe Trial Group. Neonatal Refeeding Syndrome and Clinical Outcome in Extremely Low-Birth-Weight Babies: Secondary Cohort Analysis From the ProVIDe Trial. Journal of Parenteral and Enteral Nutrition. 2020. Vol. 45, No. 1. P. 65–78. DOI: 10.1002/jpen.1934 URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC7891336/
3. Blanc S., Vasileva T., Tume L. N., Baudin F., Chessel Ford C., Chaparro Jotterand C., Valla F. V. Incidence of Refeeding Syndrome in Critically Ill Children With Nutritional Support. Frontiers in Pediatrics. 2022. Vol. 10. Article 932290. DOI: 10.3389/fped.2022.932290 URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC9253668/
4. Stević M., Vlajković-Ivanović A., Petrov-Bojičić I., Ristić N., Budić I., Marjanović V., Simić D. Identification and Prevention of Refeeding Syndrome in Pediatric Intensive Care. Srpski Arhiv za Celokupno Lekarstvo. 2024. Vol. 152, No. 3–4. P. 218–223. DOI: 10.2298/SARH230725029S URL: https://scindeks.ceon.rs/article.aspx?artid=0370-81792403218S&lang=en
5. American Society for Parenteral and Enteral Nutrition (ASPEN) Board of Directors. Consensus Recommendations for Refeeding Syndrome. Nutrition in Clinical Practice. 2020. Vol. 35, No. 1. P. 178–195. DOI: 10.1002/ncp.10474 URL: https://pubmed.ncbi.nlm.nih.gov/32115791/
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