Refeeding Syndrome May Increase the Risk of Anemia of Prematurity: Is Early Enteral Nutrition the Solution?

Preterm infants are particularly vulnerable to nutritional deficiencies and electrolyte imbalances during the early stages of extrauterine life. To ensure optimal metabolic support, they often require the early initiation of "aggressive" parenteral nutrition (PN), which is a known risk factor for Refeeding Syndrome (RS), a potentially serious metabolic condition characterized by fluid and electrolyte disturbances, the most significant of which is hypophosphatemia. Hypophosphatemia can impair the metabolism, survival, and function of red blood cells, leading to a reduction in key intracellular metabolites and the development of a metabolic block that alters their quality and decreases their stability. It is therefore hypothesized that RS may contribute to the development of anemia of prematurity (AOP). At the same time, early enteral nutrition (EN) may promote metabolic adaptation and reduce exposure to the complications of prolonged parenteral support, potentially protecting against AOP. The primary aim of this study was to determine whether preterm infants who develop RS are at increased risk of AOP. A secondary aim was to evaluate whether early EN may act as a protective factor against the development of AOP.

This retrospective observational study was conducted on infants with a gestational age ≤ 34 weeks and/or birth weight ≤ 1500 g, admitted to the Neonatal Intensive Care Unit of Policlinico Umberto I-Sapienza University of Rome, between January 2015 and November 2022. Infants diagnosed with AOP were classified as cases, while those without AOP served as the control group.

A total of 412 preterm infants were enrolled (110 cases, 302 controls). Refeeding Syndrome was significantly more frequent in infants with AOP (30.9% vs. 11.6%, p < 0.001). In the logistic regression model adjusted for gestational age, RS was independently associated with AOP (OR = 2.81; 95% CI: 1.55-5.10; p < 0.001), along with gestational age ≤ 34 weeks (OR = 7.10; 95% CI: 2.13-24.0; p = 0.001). Early enteral nutrition during the first week of life was associated with a significantly lower risk of AOP (OR = 0.12; 95% CI: 0.029-0.52; p = 0.005). The association between RS and AOP was confirmed in the model adjusted for birth weight (OR = 2.06; 95% CI: 1.16-3.79; p = 0.021). Infants with AOP showed significantly higher parenteral nutrition intake, delayed initiation of enteral feeding, and later achievement of full enteral nutrition compared with controls (all p < 0.001).

RS is significantly associated with AOP in preterm infants, likely through pathophysiological mechanisms related to hypophosphatemia. Importantly, early EN may be a protective factor against AOP, suggesting that timely initiation and advancement in enteral feeding may counteract the metabolic derangements associated with intensive parenteral support. These findings support a nutritional approach that prioritizes early and progressive enteral nutrition as a strategy to reduce the risk of both RS and AOP. Further prospective studies are needed to confirm these associations and to define optimal EN protocols for this population.