Substantial improvements in the survival rates of preterm infants have highlighted the ongoing complexities of their nutritional management, which is significantly influenced by gestational age, postmenstrual age (PMA), and inherent physiological immaturity. Small preterm infants often face feeding intolerance due to gut immaturity, manifesting as gastric dysmotility and intestinal hypomotility, alongside other complicating conditions. This challenge can slow the progression toward complete enteral nutrition. Consequently, parenteral nutrition is crucial in bridging the nutritional gap while enteral feeds gradually increase. This combined approach ensures adequate nutrient delivery to meet the infant's essential needs, ultimately supporting growth and improving health outcomes (1). Key objectives are to achieve extrauterine growth rates comparable to those in utero, promote gut maturation, and optimize immediate and long-term health outcomes, including neurodevelopment (2–5). Simultaneously, careful nutritional modulation is required to mitigate the risks of excessive postnatal weight gain and potential long-term sequelae such as obesity, diabetes, and cardiovascular disorders (6, 7). This careful balance extends to macronutrient provision; for instance, studies suggest excessive protein administration early in life may be associated with adverse neurodevelopmental outcomes (8), underscoring the critical need to provide sufficient protein for growth while avoiding potential harm from excess.

For many preterm infants, particularly those born at less than 32 weeks' gestation, nutritional support typically commences with exclusive parenteral nutrition (PN). Initial management often targets a fluid intake of approximately 100 ml/kg/day, providing 46–56 kcal/kg/day. Caloric delivery via PN is subsequently advanced over the following days, with a goal of 110–130 kcal/kg/day, to adequately support extrauterine growth and meet the high metabolic demands of this population.

Current nutritional guidelines offer specific recommendations for distinct feeding stages in preterm infants. For instance, the American Academy of Pediatrics (AAP) (Table 1) recommends a minimum parenteral nutrition (PN) intake of 90 kcal/kg/day for extremely low birth weight (ELBW) infants (9). Once full enteral nutrition (EN) is achieved, caloric targets typically increase to 110–130 kcal/kg/day, often corresponding to fluid volumes approaching 150 ml/kg/day.

Despite these established benchmarks for exclusive PN and full EN, specific, evidence-based guidelines for managing nutrition during the transition phase are notably lacking, especially for ELBW infants. This transition phase is generally defined as the period when exclusive PN is slowly reduced and eventually stopped as EN volumes gradually increase.

However, a lack of agreement continues regarding the specific enteral feeding volumes that define the initiation and cessation of this critical phase. While the ultimate goal is often to reach full enteral feeds (e.g., ∼150 ml/kg/day), the transition occurs within intermediate volumes. For instance, Wang et al., in a systematic review supporting this need for definition, proposed a quantitative operational definition, suggesting the transition phase could encompass the period when minimum enteral feeding volumes increase from 30 ml/kg/day up to approximately 120 ml/kg/day (10). Nevertheless, significant variation regarding this upper threshold remains evident in clinical practice and the literature. The phase of nutrition when PN is combined with advancing enteral nutrition from 30 ml/kg/day to 120 ml/kg/day is considered the transitional phase of nutrition.

Research on the transition from parenteral to enteral nutrition in preterm infants consistently underscores the need for well-defined, evidence-based nutrient targets during this critical period. Managing nutrition in these infants is complicated by considerable variability in clinical practices worldwide. Key areas where these practices often differ include: 1.

The timing and criteria for initiating enteral feeds:

Recognizing these varying approaches emphasizes the challenges of optimizing care. However, a thorough examination of the rationale and implications for each specific variation in practice exceeds the scope of this article.

As there are specific guidelines for the parenteral and enteral phases of nutrition in infants with very low birth weight (VLBW), the provision of nutrients may remain consistent during these phases (26, 27). However, the absence of such recommendations during the transition phase of nutrition results in an inconsistent and highly variable approach to nutrition by neonatal caregivers. Miller et al. noted that overall growth was adequate during the parenteral and enteral phases of nutrition; however, growth was compromised during the transitional phase (28). Growth velocity of <10 g/kg/day was considered poor growth. The incidence of poor growth during the parenteral, enteral, and transition phases of nutrition was 22.5%, 17.1%, and 46.1%, respectively. The odds of poor growth during the transition phase of nutrition were 5.4 (95% CI: 1.66–17.52). In this study, the authors identified that growth was compromised during the transitional phase primarily due to reduced protein intake as the parenteral nutrition was weaned and enteral nutrition was introduced. The study recommends maintaining protein intake at or above 3 g/kg/day and early human milk fortification with enteral feeds at 80 ml/kg/day.

Brennan et al., in their observational study, demonstrated macronutrient and energy deficits in the transition phase of nutrition in <34 weeks preterm infants (29). The study emphasizes the implementation of a nutrition phase (PN, transition phase, and EN) rather than a chronological age (postmenstrual age) approach to identify nutrient deficits at each phase, particularly during the transition phase, when enteral feeds reach 80 ml/kg/day and early fortification of human milk is initiated.

A subsequent prospective study by the same research group used a nutrient model to identify optimal amino acid provision during the parenteral nutritional transition for preterm infants (BW ≤1,500 g, GA <34 weeks) (30). The model yielded an optimal target of 3.5 g of amino acids per 100 ml. However, the interpretation requires caution, as clarification is needed on whether this represents a target concentration within fluids or how it translates to the standard daily intake goal (g/kg/day). The stated aim of this target was to support adequate growth and prevent nutrient deficits.

In this study (30), the researchers also proposed strategies to boost protein intake during the transition, such as customized PN formulations and appropriate human milk fortification. Their protocol included a specific fluid calculation method: enteral feeds below 40 ml/kg/day did not contribute to the fluid totals used for adjusting PN rates. This was intended to maintain consistent parenteral fluid and nutrient delivery, particularly during the initiation of minimal enteral feeds.

In a separate study, Miller et al. conducted a retrospective comparative analysis (31) that implemented a targeted nutrition protocol. They compared a study group receiving concentrated PN within a restricted total fluid volume of 100 ml/kg/day to a control group with a higher total fluid volume of 140 ml/kg/day. Both groups aimed for similar nutritional goals, targeting an energy intake of 100–120 kcal/kg/day and a protein intake greater than 3 g/kg/day, with intravenous lipids providing less than 50% of the calories derived from PN.

The weight-for-age z scores at birth, one week old, and during the transition phase were similar between groups. The findings revealed that the study group (restricted fluids with concentrated PN) achieved significantly higher weight-for-age z-scores by the end of the transition phase compared to the control group, with this advantage persisting until 35 weeks postmenstrual age. However, the authors noted that the actual delivery of protein and calories often fell short of targets when infants received total enteral feed volumes between approximately 100–130 ml/kg/day. This shortfall was potentially linked to the protocol's threshold for initiating human milk fortification, which was delayed until enteral volumes reached 100–120 ml/kg/day.

A similar correlation of the critical role of protein during the transition phase was highlighted by Liotto and the group in their NICU (32). The authors noted that very low birth weight infants with adequate growth velocity of at least 15 g/kg/day had higher enteral protein intake during the main parenteral period and higher parenteral protein and energy intakes during the main enteral nutritional intake period, suggesting a careful adjustment of protein during the transition phase.

To understand the potential risk of poor growth in the transition nutrition phase in very low birth weight infants, Immeli and group conducted a retrospective cohort study (33). The study highlights that the prolonged transition phase from parenteral to enteral nutrition correlates with lower cumulative intakes of energy, protein, fat, and carbohydrates at 28 days of age. The study specifically demonstrated that a prolonged transition phase of over 12 days in VLBW infants resulted in significantly lower weight and head circumference z-score changes at term-equivalent age compared to those with a shorter transition phase of 7 days. The study also reported more negative associations with the transition duration in boys than in girls. Interestingly, in another retrospective study by Alur et al., female ELBW infants experienced a significant decrease in weight percentiles during the transition phase compared to males with similar calorie and protein intake (34).

We designed a new approach to nutrient provision for ELBW infants, carefully considering the challenges previously outlined (25–32). Building on this foundation and the studies discussed above, we suggest a practical strategy for the transition phase (TP), which includes concentrating PN, fortifying human milk earlier, and reducing the overall duration of the TP (35): (A)

Parenteral nutrition is initiated immediately at birth with 3.5 g/kg/day of amino acids in preterm infants with birth weights of 1,000–1,500 grams and 2.5–3 g/kg/day in preterm infants with BW of <1,000 grams (1), and 100 ml/kg/day of PN.

The total calories provided at 100 ml/kg/day of PN [Dextrose10%w and 3.5 g/kg/day of amino acids (AA)] and 50 ml/kg/day of 24 kcal/oz mother's milk (BM-24) or donor breast milk will be 88 kcal/kg/day, and with lipids at 3 g/kg/day will provide 118 kcal/kg/day (Table 2).

When enteral feeds are advanced to 100 ml/kg/day and lipids are discontinued, the PN will be at 50 ml/kg/day to provide a total calories of 104 kcal/kg/day. When the PN is discontinued at 120 ml/kg/day of the enteral volume of BM-24, the total calories provided will be 110 kcal/kg/day as noted (refer to the table with nutritional characteristics). The total combined protein would be between 4.4 and 4.9 g/kg/day. The higher protein provided during the transition phase may help mitigate the first-pass effect (24, 25, 41), and the consensus suggests that increasing enteral intake by up to 50% will have a minimal impact on the systemic availability of amino acids (24). Thus, throughout the transition phase, adequate calories and protein are provided.

We also strongly recommend that a randomized controlled trial of the transition phase of nutrition may help clarify the optimal approach.

In summary, extremely low birth weight infants, in particular, and those who experienced fetal growth restriction, are at risk for poor postnatal growth and require tailored nutritional interventions (38). Hence, neonatal caregivers should pay careful attention to the five challenges outlined: timing of initiating enteral feeds, rate of advancement of enteral feed volumes, enteral volumes at which human milk fortification is introduced, timing of discontinuation of ILE, and enteral volumes at which PN is discontinued for streamlining the nutrient delivery during TP.

Addressing these challenges with diligence is crucial for streamlining nutrient delivery. Our proposed TP phase policy offers a framework for developing robust TP nutrition guidelines.

Every neonatal unit caring for ELBW infants needs to create its specific nutritional guidelines for the transition phase. This ensures a seamless shift from parenteral to enteral nutrition and helps minimize postnatal growth failure. We strongly advocate for multicenter prospective trials to identify the most effective nutritional approaches during this critical period.