ORIGINAL RESEARCH

published: 10 March 2022

doi: 10.3389/fped.2022.775667

Transition From Parenteral to Enteral

Nutrition and Postnatal Growth in
Very Preterm Infants During Their
First 28 Days of Life
Na Wang 1 , Jia Zhang 1 , Bo Wang 1 , Zhangbin Yu 2*, Shuping Han 2 , Huaiyan Wang 3 ,
Rongrong Chen 4 , Li Gu 4 , Yan Gao 5 , Weiwei Hou 6 and Xingxing Lu 6
1
Department of Pediatrics, The Affiliated Suqian First People’s Hospital of Nanjing Medical University, Suqian, China,
2
Department of Neonatology, Nanjing Maternity and Child Health Care Hospital, Women’s Hospital of Nanjing Medical
University, Nanjing, China, 3 Department of Neonatology, Changzhou Maternity and Child Health Care Hospital, Changzhou,
China, 4 Department of Neonatology, Nantong Maternity and Child Health Care Hospital, Nantong, China, 5 Department of
Neonatology, Lianyungang Maternity and Child Health Care Hospital, Lianyungang, China, 6 Department of Neonatology,
Northern Jiangsu People’s Hospital, Yangzhou, China

Background: Nutrition practices for preterm infants during the first few weeks of life
Edited by: can be divided into three phases: the parenteral nutrition (PN), enteral nutrition (EN),
Letizia Capasso,
Federico II University Hospital, Italy
and transition (TN) phases; the TN phase includes both PN and EN. Our purpose was
Reviewed by:
to analyze nutrition practices for very preterm infants during the TN phase and their
Gianluca Terrin, association with the infants’ growth during the first 28 days of life.
University of Rome La Sapienza, Italy
Changwon Choi, Methods: Data from 268 very preterm infants < 32 weeks old from six neonatal intensive
Seoul National University Bundang care units were analyzed retrospectively. The TN phase was defined as enteral feedings of
Hospital, South Korea
30-120 ml/kg/d. Postnatal growth failure (PGF) was defined as a 28-day growth velocity
*Correspondence:
Zhangbin Yu
< 15 g/kg/d. Differences in protein and energy intake between the PGF and non-PGF
[email protected] groups during the TN phase were calculated, and risk factors for PGF were identified
using multivariate regression analysis.
Specialty section:
This article was submitted to Results: The total protein (parenteral + enteral) intake during the TN was 3.16 (2.89,
Neonatology, 3.47) g/kg/d, which gradually decreased as the enteral feeding volume increased in the
a section of the journal
Frontiers in Pediatrics TN phase. The total energy (parenteral + enteral) intake during the TN phase was 115.72
Received: 14 September 2021
(106.98, 122.60) kcal/kg/d. The PGF group had a lower total protein intake (parenteral
Accepted: 07 February 2022 + enteral) than the non-PGF group had [3.09 (2.85, 3.38) g/kg/d vs. 3.27 (3.06, 3.57)
Published: 10 March 2022
g/kg/d, P = 0.007, respectively]. No significant difference was found in energy intake
Citation:
during the TN phase. The variables associated with PGF included a lower total protein
Wang N, Zhang J, Wang B, Yu Z,
Han S, Wang H, Chen R, Gu L, Gao Y, (parenteral + enteral) intake, a smaller day of age at the end of the TN phase, and a
Hou W and Lu X (2022) Transition higher birth weight z-score.
From Parenteral to Enteral Nutrition
and Postnatal Growth in Very Preterm Conclusion: Increasing the total protein intake (parenteral + enteral) during the TN could
Infants During Their First 28 Days of
reduce the incidence of PGF.
Life. Front. Pediatr. 10:775667.
doi: 10.3389/fped.2022.775667 Keywords: enteral nutrition, parenteral nutrition, premature [MeSH], growth, first 28 days of life

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Wang et al. Transition Nutrition and Growth

INTRODUCTION Nutrition Management

Infants received PN within 24 h after birth, and their initial
Postnatal growth failure (PGF) is prevalent among very preterm glucose dose of 4-8 mg/kg/min was increased by 1-2 mg/kg/min,
infants (1, 2), and the risk of developing adverse metabolic up to 11-14 mg/kg/min. Their AA intake was increased from
and neurodevelopmental outcomes later in life is high (3). 1.5-2.0 to 3.5-4.0 g/kg/d; lipids were started at 1.0 g/kg/d and
In a longitudinal cohort study of the long-term growth of increased by 0.5-1.0 g/kg/d, up to 3 g/kg/d.
preterm infants, Andrews et al. (4) concluded that early PGF Infants without contraindications to EN support should
can be prevented. Hence, the importance of early nutritional receive minimal enteral nutrition as early as possible after birth,
management for the prevention of early growth failure among with human milk or formula (10-20 ml/kg/d for 3-5 days). Full
preterm infants has been gradually recognized (1, 5). The EN is achieved when the EN calorie intake is at least 80 kcal/kg/d.
implementation of an enhanced parenteral nutrition (PN) The target caloric value of full PN is 80-100 kcal/kg/d, and the
protocol was found to promote growth, but it was also associated target caloric value of full EN is 110-135 kcal/kg/d (20).
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 Data Collection and Definitions
particularly important for preterm infants to achieve appropriate The TN phase began with the reduction of PN, i.e., an EN volume
nutrition intake and growth during their first few weeks of life. of 30-120 ml/kg/d (≥30 ml/kg/d, ≤120 ml/kg/d). The PN phase
Actual nutrition practices for preterm infants during their before the TN included a minimal volume of EN and a PN-only
first few weeks of life can be divided into three phases: the phase. Full EN was defined as an EN volume > 120 ml/kg/d or
parental nutrition (PN), enteral nutrition (EN), and transition the absence of a PN infusion.
(TN) phases, with the TN including both the PN and EN (12). Data on the nutrient intake of all intravenous and enteral
Nutrition during the TN phase is a new challenge for neonatal products during the TN phase and daily body weights were
physicians because it involves the transformation of parenteral collected retrospectively to evaluate the intake of intestinal
amino acid (AA) to enteral protein (13–17). Liotto et al. (14) protein and energy, parenteral AA and energy, and total protein
found that intensified nutritional management during the TN and energy. An EN volume of 30 ml/kg/d, which was considered
improved the postnatal growth of preterm infants. Moreover, equivalent to 30-39 ml/kg/d, was fed to the infants. When
a high incidence of poor growth during the TN predicted the feeding amount was the same for more than 1 day, the
growth failure at discharge. However, poor growth during the daily nutrient intake on these days was divided by the infant’s
PN phase was not significantly associated with growth failure at body weight of that day, and the average of these nutrients
discharge (18). in the feeding volume was calculated as the average nutrient
Martin et al. (19) reported improved growth during the composition of the feeding volume.
neonatal period by optimizing the early nutrition of preterm Growth indicators included birth weight, gestational age, time
infants, but the relationship between nutrition during the TN to regain birth weight, and growth velocity (GV). Being small
phase and growth during the neonatal period remains unknown. for gestational age was defined as a birth weight less than the
The purpose of our study was to assess the nutritional status of 10th percentile for gestational age (21). The birth weight z-
preterm infants during the TN phase and examine its association score was calculated using an online preterm growth calculator
with growth during the neonatal period. (available at www.peditools.org.) (22), and the formula was: z-
score = (the individual value – mean value)/standard deviation.
MATERIALS AND METHODS The GV (from birth to the 28th day of life) was based on an
exponential model of regaining birth weight. The formula was:
Study Design and Population GV = [1,000∗ ln (W28 /W)]/(28-D); where W28 = weight on the
This retrospective multicenter cohort study included six tertiary- 28th day of life, W = birth weight, and D = the day (of age)
care neonatal intensive care units (NICUs). Four NICUs were that birth weight was regained (23). The term PGF was defined
located in maternal and child health hospitals in Jiangsu, China: as a 28-day GV < 15 g/kg/d. The term non-PGF was defined as a
Nanjing Maternal and Child Health Hospital/Women’s Hospital 28-day GV ≥ 15 g/kg/d (24).
of Nanjing Medical University, Changzhou Maternal and Child Feeding types included human milk and formula; human
Health Hospital, Nantong Maternal and Child Health Hospital, milk included mother’s own milk (MOM) and donated human
and Lianyungang Maternal and Child Health Hospital. Two milk (DHM). When the volume of human milk reached 50-
NICUs were in general hospitals: Northern Jiangsu People’s 100 ml/kg/d, human milk fortifiers (HMFs) were added as
Hospital and the Affiliated Suqian First People’s Hospital of supplements (20). The formula included: formula for preterm
Nanjing Medical University, both of them in Jiangsu, China. infants, extensively hydrolyzed infant formula and amino acid-
Participants were recruited from January to December 2019. based formula. The protein and energy components of the
Infants included in the study were those born before 32 weeks human milk were calculated in accordance with the respective
of gestation, admitted to the NICU within 24 h of birth, and nutrient reference values of transitional milk, mature milk,
discharged after at least 28 days in the NICU. Infants who and donated milk (25, 26). The nutrient composition of the
did not achieve full enteral feeding by the 28th day after birth formula and HMFs were calculated according to the products’
were excluded. instructions (Table 1).

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Wang et al. Transition Nutrition and Growth

TABLE 1 | Calculations of the protein and energy in the human milk/formula. were performed using SPSS statistical software, version 26 (IBM
Corp. Armonk, NY).
Human milk/formula Protein Energy
composition (per 100 ml) (g) (kcal)
RESULTS
Human Transitional milk (MOM) 1.50 67.00
milk Study Population
Half fortified transitional 2.22/2.00 75.70/74.04 In 2019, 742 preterm infants were treated in the six NICUs; 474
milka/b were excluded from the study: 294 because their length of stay
Standard fortified 2.94/2.50 84.40/81.08 was <28 days, 10 because complete data were not available, 2
transitional milka/b
because their admission to the NICU was >24 h after birth, and
Mature milk (MOM) 1.20 72.00
168 because they had not completed the TN by the 28th day after
Half fortified mature 1.92/2.70 80.70/79.04
birth. Thus, data from the remaining 268 infants were included
milka/b
in this study.
Standard fortified 2.64/2.20 89.40/86.08
mature milka/b
Participants’ demographic characteristics and clinical
DHM 0.90 66.00
outcomes are compared in Table 2. Birth weight and birth
weight z-scores were significantly higher in the PGF group than
Half fortified DHMa/b 1.62/1.40 74.70/73.04
those in the non-PGF group (P = 0.001, P = 0.013, respectively),
Standard fortified 2.34/1.90 83.40/80.08
DHMa/b but none of the clinical outcomes was significantly different.
Formula Amino acid-based 2.00 67.00
formulac Comparisons of the Nutritional Data
Extensively hydrolyzed 2.00 67.00 Infants with PGF had a longer start time for the parenteral AA
infant formulad (P = 0.029), a smaller day of age at the end of the TN (P =
Formula for preterm 2.04 73.20 0.045), a lower AA intake during the PN phase (P = 0.01), and
infantse a lower total protein intake (PN + EN) during the TN phase (P
MOM, mother’s own milk; DHM, donated human milk.
= 0.007) than those without PGF. No significant difference was
a/b Human milk (maternal or donor) fortifiers, FM85® , Nestle, Swiss/Similac® , Abbott, US; found in feeding types or other nutritional data during the TN
c Amino acid-based formula, Neocate® , Nutricia, Great Britain, d Extensively hydrolyzed
phase (Table 3).
infant formula, Alfare® , Nestle, Netherlands; e Formula for preterm infants, Prenan® , During the TN phase, with the increase in the enteral feeding
Nestle, Germany.
volume, the energy and protein provided by the PN gradually
decreased, and the energy and protein provided by the EN
gradually increased, as shown in Figure 1. When the enteral
Energy calculations of parenteral nutrition were as follows: feeding volume reached 80 ml/kg/d, the protein and energy
glucose = 4 kcal/g (glucose injection); AA = 4 kcal/g (6% provided by the PN was equivalent to that provided by the
pediatric compound amino acid injection 18AA-I/19AA-I); and EN. Total protein (parenteral + enteral) during the TN phase
lipids = 9 kcal/g (20% medium and long-chain fat emulsion was 3.16 (2.89, 3.47) g/kg/d, which gradually decreased with
injection, C8−24 Ve). During the PN-dominant TN phase, the the increase in the enteral feeding volume. The total energy
amino acids in the PN were expressed as protein (1 g protein = (parenteral + enteral) intake during the TN phase was 115.72
1.13 g AA) to calculate the total protein. (106.98, 122.60) kcal/kg/d.
Infants in the PGF group had a lower parenteral AA intake
throughout the TN phase than those in the non-PGF group.
Clinical Factors Before the enteral feeding volume reached 80 ml/kg/d, the infants
The clinical factors associated with growth outcomes included
in the PGF group had a lower parenteral AA intake [2.85 (2.44,
bronchopulmonary dysplasia (BPD), with continuing oxygen
3.20) g/kg/d vs. 3.07 (2.60, 3.46) g/kg/d, P = 0.025, respectively]
requirements at 36 weeks corrected gestational age (27),
and a lower enteral protein intake [0.82 (0.77, 0.89) g/kg/d
necrotizing enterocolitis (NEC) ≥ grade 2 (28), intraventricular
vs. 0.84 (0.81, 0.92) g/kg/d, P = 0.03, respectively). After the
hemorrhage (IVH) ≥ grade 3/periventricular leukomalacia (29),
enteral feeding volume reached 80 ml/kg/d, infants in the PGF
confirmed sepsis (30) and invasive mechanical ventilation.
group had a lower parenteral AA intake [1.30 (1.01, 1.69) g/kg/d
vs.1.40 (1.20, 1.68) g/kg/d, P = 0.048, respectively]. No significant
Statistical Analysis difference was found in the parenteral or enteral energy intake
Continuous variables were expressed as median and interquartile before or after the enteral feeding volume reached 80 ml/kg/d (P
range (IQR), and categorical variables were expressed as > 0.05).
frequencies and percentages. The Mann-Whitney U and Chi-
square tests or Fisher’s exact test were used to analyze differences Predictors of Postnatal Growth Failure in
between groups. Variables with statistically significant differences the First 28 Days of Life
in the univariate analysis were entered into the multivariate We performed a multivariate logistic regression analysis of the
logistic regression model to determine the factors predicting nutritional predictors of PGF during the first 28 days of life
PGF. P < 0.05 was considered statistically significant. All analyses (Table 4). Three variables were kept in the model (P < 0.001):

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Wang et al. Transition Nutrition and Growth

TABLE 2 | Comparisons of baseline characteristics and clinical outcomes.

Total GV ≥ 15 g/kg/d GV< 15 g/kg/d P-value

(n = 268) (n = 71) (n = 197)

Birth weight z-score 0.42 (−0.08,0.89) 0.29(−0.39,0.70) 0.46(0.03,0.95) 0.013a*

Birth weight, median (IQR), g 1,290(1,160,1,490) 1,210(1,110,1,380) 1,330(1,170,1,525) 0.001a
Gestational age, median (IQR), weeks 29(28,30) 29(28,30) 29(28,30) 0.145a
Male sex, n (%) 133(49.6) 44(61.9) 89(45.1) 0.015b
Small for gestational age, n (%) 2(0.75) 1(1.41) 1(0.51) 0.460b
Time to regain birth weight, median (IQR), days 9(7,11) 8(7,11) 9(7.5,11) 0.518a
BPD, n (%) 87(32.46) 29(40.85) 58(29.4) 0.394c
NEC (≥grade 2), n (%) 18(6.72) 6(8.45) 12(6.09) 0.497c
IVH (≥grade 3)/PVL, n (%) 17(6.34) 3(4.23) 14(7.11) 0.394c
Confirmed sepsis, n (%) 20(7.46) 8(11.27) 12(6.09) 0.156c
Invasive mechanical ventilation, n (%) 59(22.01) 15(21.13) 44(22.34) 0.833c

IQR, interquartile range; BPD, bronchopulmonary dysplasia; NEC, necrotizing enterocolitis; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; GV, growth velocity; PGF,
postnatal growth failure.
a Mann-Whitney U-test; b Fisher’s exact test; c Chi-square test.
* P < 0.05, significant difference between groups.

the total protein intake (PN + EN) during the TN (P = 0.005), intake during the TN phase, resulting in a longer period of PN
the day of age at the end of the TN (P = 0.006), and the birth intake. Furthermore, our study found that the birth weight z-
weight z-score (P = 0.017). For every 0.1 g/kg/d increase in the score was negatively correlated with the GV because the preterm
total protein intake during the early TN phase, the risk for 28-day infants with a lower birth weight z-score often had a higher
growth failure decreased by 8.3%. 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
DISCUSSION reported by Izquierdo et al. (2).
The introduction and promotion of the enteral feeding of
This study analyzed the nutrition data of very preterm infants preterm infants with NEC is a major modifiable risk factor (34),
from six NICUs, excluding data from preterm infants who were which undoubtedly affects the outcomes of preterm infants with
still in the TN phase at their 28th day of life. Analysis of the NEC (35). Despite newer and gentler modes of ventilation, BPD
relationship between nutrition intake during the TN phase and remains a major cause of neonatal mortality and morbidity (36).
the growth of very preterm infants during the first 4 weeks of life Preterm infants with BPD often show better postnatal growth
showed that lack of protein during the TN phase was associated because of continued PN (37). Therefore, NEC, BPD, and the
with growth failure during the first 28 days. This finding differs other clinical factors analyzed in this study may be related to the
from those of previous studies on the nutrition and growth of growth of preterm infants. Our study population included very
preterm infants (1, 10, 19, 26). Previous studies have reported that preterm infants who had completed the TN phase during the
achieving adequate nutritional intake during the first few weeks neonatal period and achieved full enteral feeding. The inclusion
of life is challenging for preterm infants, and a potential strategy criteria precluded neonates with severe clinical outcomes during
to solve this problem is to start parenteral nutrition early, i.e., the neonatal period; therefore, no adverse outcomes (e.g., NEC or
shortly after birth (31, 32). Our study found that preterm infants BPD) were identified as risk factors in the multivariate analysis of
without PGF started parenteral nutrition earlier than infants with 28-day growth failure.
PGF did, and their amino acid intake during the PN phase was In a systematic review of GV calculations, the most commonly
higher; however, neither factor predicted growth failure during used measurement for calculating growth was g/kg/d (38). In
the neonatal period. In our study, the nutrition of preterm infants our study, we found that birth weight was an important variable
was divided by nutritional phase rather than by postnatal period. affecting PGF. However, the GV was based on an exponential
We found that protein deficiency was most likely to occur in the calculation combined with the time to regain birth weight (39).
TN phase. Therefore, total protein intake (PN + EN) during the The formula itself contained two important variables: birth
TN can predict growth failure during the neonatal period, while weight and the time to regain birth weight, which were beneficial
total energy intake has no obvious correlation with growth during for our growth evaluations (40, 41). Therefore, it is more
the neonatal period. accurate and reasonable to conclude that insufficient protein
The median duration of the TN phase was 10 days, which is intake during the TN phase can predict growth failure during the
consistent with data from previous studies (33). The older the neonatal period.
day of age at the end of the TN phase, the lower the risk of 28-day In our study, the TN phase was defined as 30 ml/kg/d ≤ the
growth failure, which may be related to lack of enteral protein enteral feeding volume ≤ 120 ml/kg/d, and could be divided

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Wang et al. Transition Nutrition and Growth

TABLE 3 | Comparisons of the nutritional data and feeding types.

Total GV ≥ 15g/kg/d GV < 15g/kg/d P-valuea

(n = 268) (n = 71) (n = 197)

Nutritional data, median (IQR)

Time to the initiation of parenteral AA, d 1(1,1) 1(1,1) 1(1,7) 0.029*
Initial dose of parenteral AA, g/kg/d 1.98(1.32,2) 1.98(1.43,2) 1.9(1.31,2) 0.109
Highest dose of parenteral AA, g/kg/d 3.51(3.11,3.84) 3.56(3.32,3.98) 3.5(3.06,3.79) 0.161
Time to the highest dose of parenteral AA, d 6(4,9) 6(4,10) 6(4,9) 0.963
Time to the cessation of parenteral AA, d 18(14,22) 19(14,24) 17(14,22) 0.129
Time to the initiation of parenteral lipids, d 2(1,2) 2(1,2) 2(1,2) 0.141
Initial dose of parenteral lipids, g/kg/d 1.03(0.97,1.49) 1.04(0.97,1.54) 1.03(0.96,1.43) 0.363
Highest dose of parenteral lipids, g/kg/d 3.38(2.96,3.67) 3.39(2.93,3.64) 3.33(2.96,3.70) 0.633
Time to the highest dose of parenteral lipids, d 6(4,10) 5(4,11) 6(4,9) 0.314
Time to the cessation of parenteral lipids, d 17(13,21) 18(13,24) 17(13,21) 0.271
Time to the initiation of enteral feeding, d 3(2,3) 3(2,3) 3(2,3) 0.108
Time to full enteral feeding of 120 ml/kg/d, d 15(12,20) 16(12,20) 15(12,9) 0.427
Time to full enteral feeding of 150 ml/kg/d, d 20(16,25) 20(17,25) 19(1626) 0.753
Time to supplementation with HMFs, d 17(13,21) 17(13,22) 17(3,21) 0.692
Feeding volume supplemented with HMFs, ml 121(107,143) 116(107,130) 124(106,146) 0.300
Time to the initiation of the TN, d 6(5,9) 8(5,10) 6(5,9) 0.103
Day of age at the end of the TN, d 17(14,22) 18(15,23) 17(13,20.5) 0.045*
Duration of the TN, d 10(8,14) 12(9,14) 10(8,14) 0.108
Highest energy intake during the PN phase, kcal/kg/d 75.10(91.30,102.25) 96.40(82.10,103.90) 88.90(74.07,101.38) 0.066
Highest AA intake during the PN phase, g/kg/d 3.6(3.1,3.9) 3.7(3.45,4.0) 3.6(3.07,3.8.0) 0.010*
Duration of the PN phase, d 5(4,8) 7(4,9) 5(4,8) 0.103
Total protein intake (PN + EN) during the TN, g/kg/d 3.16(2.89,3.47) 3.27(3.06,3.57) 3.09(2.85,3.38) 0.007*
Total energy intake (PN + EN) during the TN, kcal/kg/d 115.72(106.98,122.60) 118.39(109.29,122.54) 115.12(106.18,122.95) 0.371
Feeding types, n (%)
Breast milk 146(54.4%) 40(56.3%) 106(53.8%) 0.714
Formula 13(4.8%) 4(5.6%) 9(4.5%) 0.750
Breast milk and formula 109(40.6%) 27(38%) 82(41.6%) 0.597

Total protein = parenteral amino acid *1.13 + enteral protein.

d, days; GV, growth velocity; HMF, human milk fortification; PN, parenteral nutrition; EN, enteral nutrition; TN, transition phase; AA, amino acid; PGF, postnatal growth failure.
a P-values are for the Mann-Whitney U-test for continuous variables and the Chi-square or Fisher’s exact test for categorical variables.
* P < 0.05, significant difference between groups.

into early and late stages by an enteral feeding volume of 80 The phase before the volume of enteral feeding that reached 30
ml/kg/d. The definition of the TN phase remained controversial ml/kg/d was the PN phase. In our study, the median of the amino
(13–18, 33). The starting point of the TN can be defined as an acid intake during the PN phase was above 3.5 g/kg/d, which
enteral feeding volume of 30 ml/kg/d because the progressive met the CSPEN Guideline’s recommendation (20); however, the
reduction of PN always occurred when the enteral feeding intake of the non-PGF group was significantly higher than that
volume reached 30 ml/kg/d (after a non-nutritive feeding) (20). of the PGF group during this phase. Hence, a higher amino acid
When the enteral feeding volume reached 120 ml/kg/d, the infusion may be beneficial to the growth of the newborn during
median total energy was 115.72 kcal/kg/d, which met the energy the PN phase.
intake recommended by the Chinese Society of Parenteral and During the following TN phase, the median total protein
Enteral Nutrition (CSPEN) Guideline (20); thus, the end-point intake gradually decreased; it was <3.5 g/kg/d. Moreover, the
definition was also reasonable. Our study found that the period PGF group had a lower parenteral AA intake throughout the
with the EN volume of 30-70 ml/kg/d was the PN-dominant TN than the non-PGF group. Thus, the common phenomenon
TN, and the period with the EN volume of 80-120 ml/kg/d was of insufficient protein intake during the TN phase predicted the
the EN-dominant TN. At the point of 80 ml/kg/d (EN volume), 28-day growth failure, which further explains the association
the parenteral and enteral energy were both about 60 kcal/kg/d. of insufficient protein intake during the TN with poor growth
Based on the point, the TN phase could be divided into early and during the neonatal period. Our study found the cut-off point
late stages, which was consistent with the study of Brennan et between the early and late stages of the TN phase (i.e., when
al. (13). the amount of enteral feeding was 80 ml/kg/d and the protein

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Wang et al. Transition Nutrition and Growth

FIGURE 1 | Changes in the parenteral and enteral protein intake, and the medians and interquartile ranges of the total parenteral and total enteral energy and protein
intake during the TN phase; IQR, interquartile range.

TABLE 4 | Risk factors identified as predictors of PGF in very preterm infants in the multivariate analysis.

Predictors of PGF Adjusted OR 95%CI P-value

Birth weight z-score 1.635 1.09-2.45 0.017*

Time to initiation of parenteral AA 3.634 0.99-13.33 0.052
Highest AA intake during the PN phase 1.42 0.69-2.91 0.34
Day of age at the end of the TN 0.905 0.84-0.97 0.006*
BPD 0.835 0.42-1.66 0.608
NEC ≥ grade 2 1.076 0.35-3.23 0.896
Total protein (PN + EN) during the TN 0.172 0.05-0.59 0.005*
Total energy (PN + EN) during the TN 1.018 0.97-1.06 0.428

OR, odds ratio; CI, confidence interval; BPD, bronchopulmonary dysplasia; NEC, necrotizing enterocolitis; PN, parenteral nutrition; EN, enteral nutrition; TN, transition phase; AA, amino
acid; PGF, postnatal growth failure.
* P < 0.05, significant difference between groups.

intake during the PN phase was greater than that of the EN phase, intake throughout the TN for very preterm infants. Therefore,
and after the volume of enteral feeding was 90 ml/kg/d and the during the TN phase, the total protein intake should reach
protein intake of the EN phase gradually exceeded that of the 3.5 g/kg/d to promote better growth among preterm infants.
PN phase) reflected the current situation of insufficient protein Although human milk feeding has a lower protein content

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Wang et al. Transition Nutrition and Growth

than formula feeding, human milk can promote the deposition protein intake during the TN phase could predict growth during
of fat-free substances, resulting in better neurodevelopment. the neonatal period, suggesting that neonatal physicians should
Therefore, human milk is still the preferred choice for preterm pay more attention to infants’ total protein intake (PN + EN)
infants during the late TN phase (42). In order to increase the during the TN phase, especially parenteral amino acid intake.
total protein intake while considering the individual differences
of preterm infants, human milk fortifiers can be used as DATA AVAILABILITY STATEMENT
supplements, as appropriate, when the human milk volume
reaches 50-100 ml/kg/d (14). At the same time, regulating The original contributions presented in the study are included
the composition of the standardized PN solutions during the in the article/supplementary material, further inquiries can be
TN phase, including carbohydrates, fats, and amino acids, can directed to the corresponding author/s.
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
ETHICS STATEMENT
extremely low-birth-weight infants, the optimal composition of This study was approved by the Research Ethics Committee of
the early PN phase to avoid PGF must be balanced against the the Women’s Hospital of Nanjing Medical University (Ethics
risk for hyperglycemia (9). Number: Ning Fulun [2016] No. 73). Written informed consent
One of the strengths of our study is its multicenter cohort from the participants’ legal guardians was not required for
with a large sample size. In addition, few studies have examined participation in this study, in accordance with national legislation
the relationship between TN nutrition, and early growth of and the institutions’ requirements.
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 AUTHOR CONTRIBUTIONS
based only on the infant’s weight and the time to regain
birth weight, without considering the infant’s length or head NW, ZY, and JZ contributed to conception and design of the
circumference. Second, the study’s retrospective observational study. NW and SH contributed to the acquisition and analysis
design and lack of randomization limits the interpretation of the of the data. BW, RC, LG, XL, HW, YG, and WH performed the
results. Furthermore, standardized nutrition guidelines for the statistical analysis. NW wrote the first draft of the manuscript. All
TN phase had not been established before the study. Thus, future authors contributed to manuscript revision, read, and approved
studies should examine the associations between the infants’ the submitted version.
nutrition during the TN phase (including carbohydrates, fats, and
amino acids) and their long-term prognoses. FUNDING
CONCLUSION This research was funded by the Nanjing Medical Science
and Technology Development Foundation (ZKX19045) and
The TN from PN to EN is a critical period for maintaining Project supported by special disease cohort of Nanjing Medical
adequate growth among preterm infants. Our study showed that University (NMUC2020037).

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