OBJECTIVES

Enteral nutrition with unfortified human milk during the first 2 postnatal weeks often leads to cumulative protein and energy deficits among preterm infants. Fortified human milk administered soon after birth could increase fat-free mass (FFM) and improve growth in these infants.

METHODS

This was a masked, randomized trial. Starting on feeding day 2, extremely preterm infants 28 weeks or younger fed maternal or donor milk were randomized to receive either a diet fortified with a human-based product (intervention group) or a standard, unfortified diet (control group). This practice continued until the feeding day when a standard bovine-based fortifier was ordered. Caregivers were masked. The primary outcome was FFM-for-age z score at 36 weeks of postmenstrual age (PMA).

RESULTS

A total of 150 infants were randomized between 2020 and 2022. The mean birth weight was 795±250 g, and the median gestational age was 26 weeks. Eleven infants died during the observation period. The primary outcome was assessed in 105 infants (70%). FFM-for-age z scores did not differ between groups. Length gain velocities from birth to 36 weeks PMA were higher in the intervention group. Declines in head circumference-for-age z score from birth to 36 weeks’ PMA were less pronounced in the intervention group.

CONCLUSIONS

In infants born extremely preterm, human milk diets fortified soon after birth do not increase FFM accretion at 36 weeks’ PMA, but they may increase length gain velocity and reduce declines in head circumference-for-age z scores from birth to 36 weeks’ PMA.

What’s Known on This Subject:

Partial enteral nutrition with unfortified human milk during the first 2 postnatal weeks can be insufficient to prevent cumulative nutritional deficits in infants born extremely preterm (28 weeks of gestation or less).

What This Study Adds:

This trial indicates that early human milk fortification increases length gain velocity and reduces declines in head circumference z scores from birth to term equivalent age among infants born extremely preterm, but it appears not to increase fat-free mass accretion.

The first 2 postnatal weeks delineate a period of a great opportunity to prevent energy and protein deficits in critically ill infants born extremely preterm at 28 weeks of gestation or less.1,2  During this critical period for growth and development, provision of protein-enriched human milk diets could prevent nutritional deficits and mitigate the effect of acute critical illness on the risk of adverse growth outcomes in these infants.3 

A sufficient intake of enteral protein during the first 2 postnatal weeks could increase protein synthesis, prevent excessive weight loss, and promote growth.2,4  Because fat-free mass (FFM) accounts for muscle, bone, brain, and other tissues built on a protein matrix, a protein-enriched human milk diet initiated soon after birth could also favor FFM accretion.5  In recent years, several studies that measured body composition with noninvasive methods such as air-displacement plethysmography (ADP)6,7  have shown that most extremely preterm infants reach term-equivalent age with decreased FFM. Observational studies have also reported that FFM gains may lower the risk of long-term complications such as neurodevelopmental impairment,8  obesity, and chronic diseases in these infants,912  but previous randomized trials have not reported the effects of early human milk fortification on FFM accretion.13,14 

It is necessary to determine the effectiveness of human milk fortification during the phase of acute critical illness among extremely preterm infants. To assess the effect of improved human milk diets on the growth of preterm infants, we conducted this double-masked, randomized controlled trial to test the hypothesis that human milk diets fortified with a human milk–based product soon after birth increase FFM accretion in infants born extremely preterm.

The Increased Milk Protein to Accrue Critical Tissue (IMPACT) trial was a parallel group, masked, randomized controlled trial with a 1:1 allocation ratio. Extremely preterm infants with a gestational age of 28 weeks or less admitted to the neonatal unit at the University of Alabama at Birmingham Hospital were eligible. Infants with major congenital anomalies and infants with a terminal illness in whom decisions to withhold or limit life support have been made were excluded. The trial was registered in ClinicalTrials.gov as NCT04325308 on March 27, 2020. The University of Alabama at Birmingham institutional review board approved this trial in July 2020 (IRB-300005089).

We screened all extremely preterm infants admitted to our neonatal unit to determine trial eligibility. To enable treatment allocation before or on feeding day 2, we obtained written parental informed consent soon after birth, preferentially within the first 48 hours after birth. We assigned infants to 1 of the study groups using computer-generated random-block sequences and numbered, opaque, sealed envelopes. We randomized twins individually. Nutrition room staff not involved in patient care opened the sealed envelopes in sequential order after receiving notification of informed consent, allocated the study intervention, and dispensed feeding syringes with labels that did not show the treatment allocation. Thus, we masked the intervention to clinicians, parents, and outcome evaluators.

Extremely preterm infants fed human milk were randomized to receive either a fortified human milk diet (intervention group) or a usual, unfortified human milk diet (control group) within the first 96 hours after birth. Infants in the intervention group received unfortified maternal or donor milk on feeding day 1 (within the first 96 hours after birth). On feeding day 2, a human milk–based fortifier that increases the energy and protein content of human milk was added (Prolact, Prolacta Bioscience, Inc, City of Industry, CA). Adding this product to human milk increased the caloric density from 20 to 24 kcal/oz and the protein content by approximately 1.2 g/dL. This practice continued until the day when a standard bovine-based human milk fortifier was ordered (Enfamil Liquid Human Milk Fortifier High Protein, Mead Johnson Nutrition, Evansville, IN). Infants in the control group received maternal or donor milk from feeding day 1 until the feeding day on which the standard bovine-based human milk fortifier was ordered.

This trial compared the 2 human milk diets during the first 2 postnatal weeks under ordinary clinical circumstances without trying to control other interventions strictly. Therefore, all other intensive care and nutrition aspects were provided at clinicians’ discretion. The feeding protocol in our neonatal unit recommends early administration of oropharyngeal colostrum; administration of enteral feeds as intermittent bolus gavage every 3 hours; initiation of enteral feeds with either maternal or donor milk via orogastric tube within the first 96 hours after birth with 20 to 25 mL/kg/d; progression of enteral feeds with daily increments of 20 to 25 mL/kg/d on feeding day 2 until full enteral nutrition is established (>120 mL/kg/d); and addition of bovine-based fortifiers at approximately postnatal day 14 after full enteral nutrition has been established. In our unit, if maternal milk supply is insufficient, infants receive donor milk as an alternative until 32 or 33 weeks of postmenstrual age (PMA). Subsequently, they receive formula if their mothers can no longer supply their milk.

The primary efficacy outcome was FFM-for-age z score at 36 weeks’ PMA or hospital discharge (whichever occurred first) using ADP (PeaPod, Cosmed USA, Concord, CA). Body composition measurements were performed at 36 weeks’ PMA or hospital discharge if an infant no longer required significant respiratory support with mechanical ventilation, continuous positive airway pressure, or high-flow nasal cannula. Body composition measurements were converted into z score values using updated, sex-specific reference curves of body composition in preterm infants.15  Anthropometric measurements from birth to 36 weeks’ PMA were converted into z score values using the Fenton growth curves. Secondary efficacy outcomes included significant weight loss during the first 14 days after birth (decline in weight-for-age z score from birth to 14 days >0.8),16  weight gain velocity in grams per kilogram per day from birth to 36 weeks’ PMA calculated using the exponential method, postnatal growth failure (weight <10th centile at 36 weeks’ PMA), moderate to severe malnutrition (decline in weight-for-age z score from birth to 36 weeks’ PMA >1.2),17  FFM in kilograms and percentage at 36 weeks’ PMA, fat mass in kilograms and percentage at 36 weeks’ PMA, and anthropometric measurements (weight, head circumference, and length) at 36 weeks’ PMA. Length at 36 weeks’ PMA was measured with length boards. Head circumference was measured with a flexible tape measure.

The primary safety outcomes included spontaneous intestinal perforation (SIP), necrotizing enterocolitis (NEC) stage 2 or 3, and death. A data safety and monitoring committee examined individual infant data at 25% and 50% enrollment to rule out the possibility of a temporal association between the study intervention and the primary safety outcomes.

We used data from a previous enteral feeding trial to calculate the sample size for this trial.5  To detect a 0.5 difference in FFM-for-age z scores between groups with SD of 1, 0.05 level of significance, and 80% power for a t test that compares means from 2 independent samples, we estimated that a sample size of 126 patients would be necessary for this superiority trial. Anticipating that approximately 20% of study participants would be lost to follow-up for assessment of the primary outcome at 36 weeks’ PMA, we added 12 patients to each group and increased the sample size to 150, 75 patients in each group (n = 150).

This trial recorded core data on nutrition as recommended by consensus groups.18  We used mean and SD or median and interquartile ranges (IQR) to summarize continuous variables. To summarize categorical variables, we used frequencies and proportions. We compared categorical variables with either χ2 or Fisher exact tests and continuous variables with t test. We estimated mean differences, relative risks, and their respective 95% confidence intervals to report differences between groups. For analysis of the primary outcome, an unadjusted t test comparison of the mean FFM-for-age z score between control and intervention groups was performed, assuming a normal distribution of this variable.19,20  All trial outcomes were analyzed using JMP Pro 16.1 following the intention-to-treat principle.18 

Of 230 extremely preterm infants assessed for eligibility between August 2020 and October 2022, 150 were randomized (Fig 1). Baseline characteristics of the study participants are shown in Table 1. The mean birth weight was 795 g (SD, 250), and the median gestational age was 26 weeks (IQR, 24-27). Of 150 infants included, 31 had a gestational age of 23 weeks or less (21%). Approximately one-half of infants were of non-Hispanic Black race/ethnicity. Nearly 90% of infants were exposed to at least 1 dose of antenatal steroids. The median postnatal age at consent was 48 hours (IQR, 24-72).

More than 80% of infants who participated in this trial achieved full enteral nutrition within the first 2 weeks after birth. Maternal milk intake did not differ between the intervention and control group at postnatal day 7 (91 ± 55 vs 96 ± 54 mL/kg/d; P = .58) or postnatal day 14 (127 ± 58 vs 135 ± 60 mL/kg/d; P = .37).

The primary outcome was measured in 105 of 150 infants randomized (70%) (Table 2). Approximately 90% of infants who did not require significant respiratory support with mechanical ventilation, continuous positive airway pressure, or high-flow nasal cannula at 36 weeks’ PMA had a body composition measurement. FFM-for-age z scores did not differ between groups. Length gain velocities from birth to 36 weeks’ PMA were higher in the intervention group (Table 3). Declines in head circumference-for-age z score from birth to 36 weeks’ PMA were less pronounced in the intervention group. Two post hoc exploratory analyses were performed to account for unexpected imbalances in baseline characteristics. One excluded small-for-gestational-age infants (Supplemental Table 4) and the other assessed the interaction between the study intervention and sex. The analysis adjusted for sex revealed that the direction and magnitude of the effect sizes reported in the primary analysis were not significantly different in female and male infants.

The risk of postnatal growth failure and the risk of moderate to severe malnutrition at 36 weeks’ PMA were not significantly lower in the intervention group. The risk of SIP, NEC, death, and the combined outcome of SIP, NEC, or death did not differ between groups (Table 3). The highest blood urea nitrogen values were observed at postnatal day 24 (95% confidence interval, 22-26 days). The highest blood urea nitrogen values during the first 50 days after birth did not differ between groups (33 vs 37 mg/dL; P = .37). None of the 4 cases of NEC occurred during the transition from a human-based to a bovine-based fortifier. Two infants unexposed to bovine-based fortifiers developed NEC before reaching full enteral feeding. The other 2 infants developed NEC after several weeks of exposure to bovine-based fortifiers.

In this pragmatic randomized trial, we recruited a representative sample of infants born extremely preterm, assigned the study intervention randomly, masked clinicians to the study intervention, monitored anthropometric measurements at regular intervals until term-equivalent age, and compared the mean differences in FFM accretion between the 2 groups at term equivalent age. Our analysis indicated that FFM at term equivalent age did not differ between groups. We also found that early human milk fortification reduced declines in weight-for-age z scores from birth to postnatal day 14. Additionally, we established that early human milk fortification was associated with increased length gain velocities and reduced declines in head circumference-for age z scores from birth to term-equivalent age. To our knowledge, this is the largest randomized controlled trial of early human milk fortification that includes only extremely preterm infants, a high-risk population often underrepresented in enteral feeding trials.

This trial that provides the highest level of evidence for causality addresses 2 important limitations described in the 2 most recent meta-analyses of early fortification practices: the risk of bias from lack of masking and the imprecision in efficacy outcomes observed in previous trials with smaller sample sizes.13,14  Masked randomization ensured that the groups were similar in terms of known and unknown factors. Masking also avoided differential noncompliance and minimized surveillance and ascertainment biases. Our trial had a sample size with sufficient power to detect a 0.5 mean difference in z scores between groups, a growth outcome that could be considered clinically meaningful.

The main limitations of this trial were the insufficient power to assess the potential harms of early human milk fortification and the single-center design. This trial provided valuable safety and feasibility data regarding the practice of early human milk fortification with a human-based product and the subsequent transition to a bovine-based fortifier around postnatal day 14, but our sample size had insufficient power to detect significant differences in NEC between groups. Nevertheless, the number of NEC cases reported in this trial was similar to those reported in trials of early human milk fortification that included preterm infants born at older gestational ages.21,22  This finding could be attributed to the provision of exclusive human milk diets during the first 2 postnatal weeks and human milk diets up to 32 weeks’ PMA in all infants, a feeding practice that reduces the risk of NEC.23 

The single-center design is a limitation because feeding practices may differ substantially across neonatal units. Based on current clinical evidence from meta-analyses of randomized trials designed to establish full enteral nutrition soon after birth,24,25  many neonatal units have already implemented recent recommendations regarding the early and rapid progression of enteral nutrition.1  In these units, full enteral nutrition is achieved within the first 2 weeks after birth in more than 80% of all extremely preterm infants.26,27  Both randomization groups in this trial experienced a rapid transition to full enteral nutrition and likely benefited from the early and rapid progression of enteral feeding volumes. This finding implies that the observed differences in weight, length, and head circumference following early human milk fortification were not related to fluid intake, but likely because of the early provision of additional enteral protein and renal solutes, such as sodium, chloride, calcium, and phosphorus, while establishing full enteral nutrition. In circumstances in which delays establishing full enteral nutrition are expected,21,27  particularly in growth-restricted infants,28  early human milk fortification could still favor FFM accretion. Maternal to donor milk feeding ratios may also differ across neonatal units. In infants predominantly fed donor milk, early human milk fortification with human-based products that increase energy and protein content could be more beneficial.29,30  Recent observational studies suggest that maternal milk produced during the first 14 days after preterm birth could meet energy and protein requirements without additional fortification in extremely preterm infants.31  Thus, future trials should carefully consider the issue of protein source and quality. Assuming that the effects of enteral protein intake on growth and neurodevelopment are comparable to those of parenteral protein intake could lead to inaccurate conclusions.32,33 

One of the main strengths of this trial was the intention-to-treat analysis performed. This analytic approach preserves the randomization effect and increases generalizability of our findings. The other strength was using FFM as a primary outcome measure, which is rarely reported in enteral feeding trials. Measuring this outcome at term-equivalent age could help identify nutritional practices that prevent excessive weight gain from fat mass gains, especially with the increasing availability of reference values for FFM accretion at different gestational ages.34,35  However, it is important to acknowledge that ADP-measured FFM can only be assessed in infants who do not require significant respiratory support. Therefore, information on FFM accretion in the most immature and sickest infants, who are most likely to develop nutritional deficits, is often missing. This limitation could potentially explain the poor correlation between growth and body composition outcomes reported in observational studies that included preterm infants.36,37 

This trial is the first to report significant length and head circumference gains resulting from early human milk fortification. Our finding of reduced weight z score declines during the first 2 weeks after birth is consistent with previous trials of early human milk fortification that have shown the same direction of effect in preterm infants born at older gestational ages.21,22  It also provides evidence that including the most immature infants in nutritional studies that assess growth outcomes requires careful consideration. Although including these infants in trials may help identify strategies to prevent significant weight loss during the phase of acute critical illness, these trials may not always detect significant benefits on weight or FFM gains at 36 weeks’ PMA or discharge. In this trial, more than 20% of infants included were born at 23 weeks of gestation or less. Despite not identifying a significant reduction in the risk of moderate to severe malnutrition following early human milk fortification, we reported length and head circumference gains per week that are comparable to those reported in observational studies that demonstrated successful prevention of postnatal growth failure after the gradual introduction of multiple innovative nutritional practices in a neonatal unit.38,39 

Gains in length and head circumference are critical indicators of overall growth. Length is a measure of overall body size. A larger head circumference can indicate that the brain is growing, which is crucial for cognitive and motor development. Future studies should analyze the long-term effects of early human milk fortification on growth outcomes. Our adjusted analysis revealed that early human milk fortification had similar short-term effects on FFM, weight, length, and head circumference gains in both female and male infants, but observational studies have reported slightly slower head growth40  and faster weight gain after term equivalent age in extremely preterm female infants.41  Studying the long-term effects of early human milk fortification on neurodevelopmental outcomes is also highly recommended. If the positive effects on length and head circumference observed in this trial translate into potential benefits for neurodevelopment at 2 years of age, early human milk fortification could still be justified, even if this nutritional practice does not have an impact on FFM at 36 weeks PMA.

This trial reveals that human milk diets fortified soon after birth in infants born extremely preterm do not increase FFM accretion at term-equivalent age. Early provision of fortified human milk within the first 96 hours after birth may increase length gain velocity and reduce declines in head circumference-for-age z scores from birth to 36 weeks’ PMA.

Dr Salas conceptualized and designed the study, obtained funding, carried out the initial analysis, drafted the initial manuscript, and approved the final manuscript as submitted; Dr Gunawan carried out the statistical analysis, reviewed and revised manuscript, and approved the final manuscript as submitted; Ms Nguyen and Ms Reeves designed the data collection instruments, monitored patient enrollment and compliance, collected data, performed body composition assessments, reviewed and revised manuscript, and approved the♮final manuscript as submitted; Ms Finck and Ms Argent performed the randomization, monitored compliance, reviewed the manuscript, and approved the final manuscript as submitted; Dr Carlo helped design the study, critically reviewed the manuscript, and approved the final manuscript as submitted; and all authors approved the final manuscript as submitted♮and agree to be accountable for all aspects of the work.

The Increased Milk Protein to Accrue Critical Tissue (IMPACT) trial has been registered at www.clinicaltrials.gov (identifier NCT04325308).  Deidentified individual participant data will be made available on publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to asalas@uab.edu.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2023-062391.

FUNDING: This trial was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), grant number K23HD102554. The funder did not participate in the work. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to disclose. Dr Salas patented an instrumented feeding bottle and received consulting fees for participation in Mead Johnson Nutrition advisory board meetings. Prolacta Bioscience provided the human-based fortifiers at cost and had no role in the design of the study, collection, analysis, interpretation of data, or writing of the manuscript.

ADP

air-displacement plethysmography

FFM

fat-free mass

IQR

interquartile range

NEC

necrotizing enterocolitis

PMA

postmenstrual age

SIP

spontaneous intestinal perforation

1
Embleton
ND
,
Moltu
SJ
,
Lapillonne
A
, et al
.
Enteral Nutrition in Preterm Infants (2022): a position paper from the ESPGHAN Committee on Nutrition and Invited Experts
.
J Pediatr Gastroenterol Nutr
.
2023
;
76
(
2
):
248
268
2
Embleton
NE
,
Pang
N
,
Cooke
RJ
.
Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants?
Pediatrics
.
2001
;
107
(
2
):
270
273
3
Ehrenkranz
RA
,
Das
A
,
Wrage
LA
, et al;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Early nutrition mediates the influence of severity of illness on extremely LBW infants
.
Pediatr Res
.
2011
;
69
(
6
):
522
529
4
Miller
J
,
Makrides
M
,
Gibson
RA
, et al
.
Effect of increasing protein content of human milk fortifier on growth in preterm infants born at <31 wk gestation: a randomized controlled trial
.
Am J Clin Nutr
.
2012
;
95
(
3
):
648
655
5
Salas
AA
,
Jerome
M
,
Finck
A
,
Razzaghy
J
,
Chandler-Laney
P
,
Carlo
WA
.
Body composition of extremely preterm infants fed protein-enriched, fortified milk: a randomized trial
.
Pediatr Res
.
2022
;
91
(
5
):
1231
1237
6
Demerath
EW
,
Fields
DA
.
Body composition assessment in the infant
.
Am J Hum Biol
.
2014
;
26
(
3
):
291
304
7
Ellis
KJ
,
Yao
M
,
Shypailo
RJ
,
Urlando
A
,
Wong
WW
,
Heird
WC
.
Body-composition assessment in infancy: air-displacement plethysmography compared with a reference 4-compartment model
.
Am J Clin Nutr
.
2007
;
85
(
1
):
90
95
8
Ramel
SE
,
Gray
HL
,
Christiansen
E
,
Boys
C
,
Georgieff
MK
,
Demerath
EW
.
Greater early gains in fat-free mass, but not fat mass, are associated with improved neurodevelopment at 1 year corrected age for prematurity in very low birth weight preterm infants
.
J Pediatr
.
2016
;
173
:
108
115
9
Parkinson
JR
,
Hyde
MJ
,
Gale
C
,
Santhakumaran
S
,
Modi
N
.
Preterm birth and the metabolic syndrome in adult life: a systematic review and meta-analysis
.
Pediatrics
.
2013
;
131
(
4
):
e1240
e1263
10
Euser
AM
,
Finken
MJ
,
Keijzer-Veen
MG
,
Hille
ET
,
Wit
JM
,
Dekker
FW
;
Dutch POPS-19 Collaborative Study Group
.
Associations between prenatal and infancy weight gain and BMI, fat mass, and fat distribution in young adulthood: a prospective cohort study in males and females born very preterm
.
Am J Clin Nutr
.
2005
;
81
(
2
):
480
487
11
Kerkhof
GF
,
Willemsen
RH
,
Leunissen
RW
,
Breukhoven
PE
,
Hokken-Koelega
AC
.
Health profile of young adults born preterm: negative effects of rapid weight gain in early life
.
J Clin Endocrinol Metab
.
2012
;
97
(
12
):
4498
4506
12
Morrison
KM
,
Ramsingh
L
,
Gunn
E
, et al
.
Cardiometabolic health in adults born premature with extremely low birth weight
.
Pediatrics
.
2016
;
138
(
4
):
e20160515
13
Thanigainathan
S
,
Abiramalatha
T
.
Early fortification of human milk versus late fortification to promote growth in preterm infants
.
Cochrane Database Syst Rev
.
2020
;
7
(
7
):
CD013392
14
Hilditch
C
,
Keir
A
,
Collins
CT
,
Middleton
P
,
Gomersall
J
.
Early versus delayed introduction of human milk fortification in enterally fed preterm infants: a systematic review and meta-analysis
.
J Paediatr Child Health
.
2022
;
58
(
1
):
30
38
15
Norris
T
,
Ramel
SE
,
Catalano
P
, et al
.
New charts for the assessment of body composition, according to air-displacement plethysmography, at birth and across the first 6 mo of life
.
Am J Clin Nutr
.
2019
;
109
(
5
):
1353
1360
16
Rochow
N
,
Raja
P
,
Liu
K
, et al
.
Physiological adjustment to postnatal growth trajectories in healthy preterm infants
.
Pediatr Res
.
2016
;
79
(
6
):
870
879
17
Goldberg
DL
,
Becker
PJ
,
Brigham
K
, et al
.
Identifying malnutrition in preterm and neonatal populations: recommended indicators
.
J Acad Nutr Diet
.
2018
;
118
(
9
):
1571
1582
18
Koletzko
B
,
Fewtrell
M
,
Gibson
R
, et al;
Consensus Group on Outcome Measures Made in Paediatric Enteral Nutrition Clinical Trials (COMMENT)
;
Early Nutrition Project
.
Core data necessary for reporting clinical trials on nutrition in infancy
.
Ann Nutr Metab
.
2015
;
66
(
1
):
31
35
19
Giannì
ML
,
Roggero
P
,
Liotto
N
, et al
.
Body composition in late preterm infants according to percentile at birth
.
Pediatr Res
.
2016
;
79
(
5
):
710
715
20
Atkinson
SA
,
Randall-Simpson
J
.
Factors influencing body composition of premature infants at term-adjusted age
.
Ann N Y Acad Sci
.
2000
;
904
:
393
399
21
Shah
SD
,
Dereddy
N
,
Jones
TL
,
Dhanireddy
R
,
Talati
AJ
.
Early versus delayed human milk fortification in very low birth weight infants-a randomized controlled trial
.
J Pediatr
.
2016
;
174
:
126
131.e1
22
Alizadeh Taheri
P
,
Sajjadian
N
,
Asgharyan Fargi
M
,
Shariat
M
.
Is early breast milk fortification more effective in preterm infants? A clinical trial
.
J Perinat Med
.
2017
;
45
(
8
):
953
957
23
Quigley
M
,
Embleton
ND
,
McGuire
W
.
Formula versus donor breast milk for feeding preterm or low birth weight infants
.
Cochrane Database Syst Rev
.
2019
;
7
(
7
):
CD002971
24
Morgan
J
,
Young
L
,
McGuire
W
.
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants
.
Cochrane Database Syst Rev
.
2014
;
2014
(
12
):
CD001970
25
Oddie
SJ
,
Young
L
,
McGuire
W
.
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants
.
Cochrane Database Syst Rev
.
2017
;
8
(
8
):
CD001241
26
Wiechers
C
,
Avellina
V
,
Luger
B
, et al
.
Body composition of preterm infants following rapid transition to enteral feeding
.
Neonatology
.
2022
;
119
(
2
):
246
254
27
Fenin
A
,
Newman
JC
,
Taylor
SN
.
Very low birth weight infants receive full enteral nutrition within 2 postnatal weeks
.
J Perinatol
.
2020
;
40
(
12
):
1849
1856
28
Kempley
S
,
Gupta
N
,
Linsell
L
, et al;
ADEPT Trial Collaborative Group
.
Feeding infants below 29 weeks’ gestation with abnormal antenatal Doppler: analysis from a randomised trial
.
Arch Dis Child Fetal Neonatal Ed
.
2014
;
99
(
1
):
F6
F11
29
Gates
A
,
Thompson
AB
,
Marin
T
,
Waller
JL
,
Patel
J
,
Stansfield
BK
.
Novel multinutrient human milk-based human milk fortifier promotes growth and tolerance in premature infants
.
JPEN J Parenter Enteral Nutr
.
2022
;
46
(
4
):
817
827
30
Sullivan
S
,
Schanler
RJ
,
Kim
JH
, et al
.
An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products
.
J Pediatr
.
2010
;
156
(
4
):
562
7.e1
31
Gates
A
,
Marin
T
,
De Leo
G
,
Waller
JL
,
Stansfield
BK
.
Nutrient composition of preterm mother’s milk and factors that influence nutrient content
.
Am J Clin Nutr
.
2021
;
114
(
5
):
1719
1728
32
Bloomfield
FH
,
Jiang
Y
,
Harding
JE
,
Crowther
CA
,
Cormack
BE
;
ProVIDe Trial Group
.
Early amino acids in extremely preterm Infants and Nneurodisability at 2 years
.
N Engl J Med
.
2022
;
387
(
18
):
1661
1672
33
Chmielewska
A
,
Farooqi
A
,
Domellöf
M
,
Ohlund
I
.
Lean tissue deficit in preterm infants persists up to 4 months of age: results from a Swedish Longitudinal Study
.
Neonatology
.
2020
;
117
(
1
):
80
87
34
Johnson
MJ
,
Wootton
SA
,
Leaf
AA
,
Jackson
AA
.
Preterm birth and body composition at term equivalent age: a systematic review and meta-analysis
.
Pediatrics
.
2012
;
130
(
3
):
e640
e649
35
Demerath
EW
,
Johnson
W
,
Davern
BA
, et al
.
New body composition reference charts for preterm infants
.
Am J Clin Nutr
.
2017
;
105
(
1
):
70
77
36
Kiger
JR
,
Taylor
SN
,
Wagner
CL
,
Finch
C
,
Katikaneni
L
.
Preterm infant body composition cannot be accurately determined by weight and length
.
J Neonatal Perinatal Med
.
2016
;
9
(
3
):
285
290
37
Ramel
SE
,
Zhang
L
,
Misra
S
,
Anderson
CG
,
Demerath
EW
.
Do anthropometric measures accurately reflect body composition in preterm infants?
Pediatr Obes
.
2017
;
12
(
suppl 1
):
72
77
38
Andrews
ET
,
Ashton
JJ
,
Pearson
F
,
Beattie
RM
,
Johnson
MJ
.
Early postnatal growth failure in preterm infants is not inevitable
.
Arch Dis Child Fetal Neonatal Ed
.
2019
;
104
(
3
):
F235
F241
39
Johnson
MJ
,
Leaf
AA
,
Pearson
F
, et al
.
Successfully implementing and embedding guidelines to improve the nutrition and growth of preterm infants in neonatal intensive care: a prospective interventional study
.
BMJ Open
.
2017
;
7
(
12
):
e017727
40
Zozaya
C
,
Avila-Alvarez
A
,
Arruza
L
, et al
.
The effect of morbidity and sex on postnatal growth of very preterm infants: a multicenter cohort study
.
Neonatology
.
2019
;
115
(
4
):
348
354
41
Chou
FS
,
Yeh
HW
.
Sex differences in postnatal weight gain trajectories of extremely preterm newborns
.
J Perinatol
.
2021
;
41
(
8
):
1835
1844
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits noncommercial, distribution, and reproduction in any medium, provided the original author and source are credited.

Supplementary data