Postnatal growth failure (PGF) is prevalent among very preterm infants (1, 2), and the risk of developing adverse metabolic and neurodevelopmental outcomes later in life is high (3). In a longitudinal cohort study of the long-term growth of preterm infants, Andrews et al. (4) concluded that early PGF can be prevented. Hence, the importance of early nutritional management for the prevention of early growth failure among preterm infants has been gradually recognized (1, 5). The implementation of an enhanced parenteral nutrition (PN) protocol was found to promote growth, but it was also associated with an increased prevalence of severe hyperglycemia and higher mortality (6–9). Appropriate postnatal growth is more likely to be followed by better long-term outcomes (10, 11); therefore, it is particularly important for preterm infants to achieve appropriate nutrition intake and growth during their first few weeks of life.

Actual nutrition practices for preterm infants during their first few weeks of life can be divided into three phases: the parental nutrition (PN), enteral nutrition (EN), and transition (TN) phases, with the TN including both the PN and EN (12). Nutrition during the TN phase is a new challenge for neonatal physicians because it involves the transformation of parenteral amino acid (AA) to enteral protein (13–17). Liotto et al. (14) found that intensified nutritional management during the TN improved the postnatal growth of preterm infants. Moreover, a high incidence of poor growth during the TN predicted growth failure at discharge. However, poor growth during the PN phase was not significantly associated with growth failure at discharge (18).

Martin et al. (19) reported improved growth during the neonatal period by optimizing the early nutrition of preterm infants, but the relationship between nutrition during the TN phase and growth during the neonatal period remains unknown. The purpose of our study was to assess the nutritional status of preterm infants during the TN phase and examine its association with growth during the neonatal period.

This study analyzed the nutrition data of very preterm infants from six NICUs, excluding data from preterm infants who were still in the TN phase at their 28th day of life. Analysis of the relationship between nutrition intake during the TN phase and the growth of very preterm infants during the first 4 weeks of life showed that lack of protein during the TN phase was associated with growth failure during the first 28 days. This finding differs from those of previous studies on the nutrition and growth of preterm infants (1, 10, 19, 26). Previous studies have reported that achieving adequate nutritional intake during the first few weeks of life is challenging for preterm infants, and a potential strategy to solve this problem is to start parenteral nutrition early, i.e., shortly after birth (31, 32). Our study found that preterm infants without PGF started parenteral nutrition earlier than infants with PGF did, and their amino acid intake during the PN phase was higher; however, neither factor predicted growth failure during the neonatal period. In our study, the nutrition of preterm infants was divided by nutritional phase rather than by postnatal period. We found that protein deficiency was most likely to occur in the TN phase. Therefore, total protein intake (PN + EN) during the TN can predict growth failure during the neonatal period, while total energy intake has no obvious correlation with growth during the neonatal period.

The median duration of the TN phase was 10 days, which is consistent with data from previous studies (33). The older the day of age at the end of the TN phase, the lower the risk of 28-day growth failure, which may be related to lack of enteral protein intake during the TN phase, resulting in a longer period of PN intake. Furthermore, our study found that the birth weight z-score was negatively correlated with the GV because the preterm infants with a lower birth weight z-score often had a higher parenteral amino acid intake during the PN-only and TN phases. This finding is consistent with the negative correlation between birth weight z-score and changes in the birth weight z-scores reported by Izquierdo et al. (2).

The introduction and promotion of the enteral feeding of preterm infants with NEC is a major modifiable risk factor (34), which undoubtedly affects the outcomes of preterm infants with NEC (35). Despite newer and gentler modes of ventilation, BPD remains a major cause of neonatal mortality and morbidity (36). Preterm infants with BPD often show better postnatal growth because of continued PN (37). Therefore, NEC, BPD, and the other clinical factors analyzed in this study may be related to the growth of preterm infants. Our study population included very preterm infants who had completed the TN phase during the neonatal period and achieved full enteral feeding. The inclusion criteria precluded neonates with severe clinical outcomes during the neonatal period; therefore, no adverse outcomes (e.g., NEC or BPD) were identified as risk factors in the multivariate analysis of 28-day growth failure.

In a systematic review of GV calculations, the most commonly used measurement for calculating growth was g/kg/d (38). In our study, we found that birth weight was an important variable affecting PGF. However, the GV was based on an exponential calculation combined with the time to regain birth weight (39). The formula itself contained two important variables: birth weight and the time to regain birth weight, which were beneficial for our growth evaluations (40, 41). Therefore, it is more accurate and reasonable to conclude that insufficient protein intake during the TN phase can predict growth failure during the neonatal period.

In our study, the TN phase was defined as 30 ml/kg/d ≤ the enteral feeding volume ≤ 120 ml/kg/d, and could be divided into early and late stages by an enteral feeding volume of 80 ml/kg/d. The definition of the TN phase remained controversial (13–18, 33). The starting point of the TN can be defined as an enteral feeding volume of 30 ml/kg/d because the progressive reduction of PN always occurred when the enteral feeding volume reached 30 ml/kg/d (after a non-nutritive feeding) (20). When the enteral feeding volume reached 120 ml/kg/d, the median total energy was 115.72 kcal/kg/d, which met the energy intake recommended by the Chinese Society of Parenteral and Enteral Nutrition (CSPEN) Guideline (20); thus, the end-point definition was also reasonable. Our study found that the period with the EN volume of 30-70 ml/kg/d was the PN-dominant TN, and the period with the EN volume of 80-120 ml/kg/d was the EN-dominant TN. At the point of 80 ml/kg/d (EN volume), the parenteral and enteral energy were both about 60 kcal/kg/d. Based on the point, the TN phase could be divided into early and late stages, which was consistent with the study of Brennan et al. (13).

The phase before the volume of enteral feeding that reached 30 ml/kg/d was the PN phase. In our study, the median of the amino acid intake during the PN phase was above 3.5 g/kg/d, which met the CSPEN Guideline's recommendation (20); however, the intake of the non-PGF group was significantly higher than that of the PGF group during this phase. Hence, a higher amino acid infusion may be beneficial to the growth of the newborn during the PN phase.

During the following TN phase, the median total protein intake gradually decreased; it was <3.5 g/kg/d. Moreover, the PGF group had a lower parenteral AA intake throughout the TN than the non-PGF group. Thus, the common phenomenon of insufficient protein intake during the TN phase predicted the 28-day growth failure, which further explains the association of insufficient protein intake during the TN with poor growth during the neonatal period. Our study found the cut-off point between the early and late stages of the TN phase (i.e., when the amount of enteral feeding was 80 ml/kg/d and the protein intake during the PN phase was greater than that of the EN phase, and after the volume of enteral feeding was 90 ml/kg/d and the protein intake of the EN phase gradually exceeded that of the PN phase) reflected the current situation of insufficient protein intake throughout the TN for very preterm infants. Therefore, during the TN phase, the total protein intake should reach 3.5 g/kg/d to promote better growth among preterm infants. Although human milk feeding has a lower protein content than formula feeding, human milk can promote the deposition of fat-free substances, resulting in better neurodevelopment. Therefore, human milk is still the preferred choice for preterm infants during the late TN phase (42). In order to increase the total protein intake while considering the individual differences of preterm infants, human milk fortifiers can be used as supplements, as appropriate, when the human milk volume reaches 50-100 ml/kg/d (14). At the same time, regulating the composition of the standardized PN solutions during the TN phase, including carbohydrates, fats, and amino acids, can achieve the goal of optimal nutrient intake to improve the growth of preterm infants during the neonatal period (13, 14). Moreover, considering the high mortality rate caused by hyperglycemia in extremely low-birth-weight infants, the optimal composition of the early PN phase to avoid PGF must be balanced against the risk for hyperglycemia (9).

One of the strengths of our study is its multicenter cohort with a large sample size. In addition, few studies have examined the relationship between TN nutrition, and early growth of preterm infants. We also reported the current situation of insufficient protein intake during the TN phase. However, there are some limitations. First, the growth assessment was based only on the infant's weight and the time to regain birth weight, without considering the infant's length or head circumference. Second, the study's retrospective observational design and lack of randomization limits the interpretation of the results. Furthermore, standardized nutrition guidelines for the TN phase had not been established before the study. Thus, future studies should examine the associations between the infants' nutrition during the TN phase (including carbohydrates, fats, and amino acids) and their long-term prognoses.

The TN from PN to EN is a critical period for maintaining adequate growth among preterm infants. Our study showed that protein intake during the TN phase could predict growth during the neonatal period, suggesting that neonatal physicians should pay more attention to infants' total protein intake (PN + EN) during the TN phase, especially parenteral amino acid intake.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

This study was approved by the Research Ethics Committee of the Women's Hospital of Nanjing Medical University (Ethics Number: Ning Fulun [2016] No. 73). Written informed consent from the participants' legal guardians was not required for participation in this study, in accordance with national legislation and the institutions' requirements.

NW, ZY, and JZ contributed to conception and design of the study. NW and SH contributed to the acquisition and analysis of the data. BW, RC, LG, XL, HW, YG, and WH performed the statistical analysis. NW wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

This research was funded by the Nanjing Medical Science and Technology Development Foundation (ZKX19045) and Project supported by special disease cohort of Nanjing Medical University (NMUC2020037).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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