The Effects of Different Enteral Feeding Regimens on Necrotizing Enterocolitis, Mortality, and Neurodevelopment in Very Preterm Infants: A Multicenter Double-Randomized Trial
Phase: NA
Conditions: Very Preterm Infant, Necrotizing Enterocolitis (NEC)
Sponsor: The Children's Hospital of Zhejiang University School of Medicine

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The Effects of Different Enteral Feeding Regimens on Necrotizing 
Enterocolitis, Mortality, and Neurodevelopment in Very Preterm 
Infants: A Multicenter Double-Randomized Trial 
 
 
 
 
 
 
 
 
 
Research Proposal 
Nov.26, 2025 
 
 
 
 
 
 
 
 
 
 
 

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I. Research Background 
Necrotizing enterocolitis (NEC) is one of the most severe and life-threatening gastrointestinal 
diseases affecting preterm infants, characterized by high mortality, a high rate of surgical 
intervention, and the risk of long-term neurodevelopmental impairment [1]. In China, it is estimated 
that 50,000 to 60,000 preterm infants with a gestational age of less than 29 weeks are born each 
year, among whom several thousand may develop NEC. A significant proportion of these cases 
require surgical intervention or result in death [2-4]. Additionally, many more preterm infants 
experience milder forms of NEC, which, although not fatal, can disrupt enteral feeding, prolong 
hospitalization, increase antibiotic exposure, and lead to substantial healthcare costs. 
 
Feeding practices are considered a key modifiable risk factor for NEC. While own mother’s 
milk (OMM) is the standard feeding recommendation and offers some protective effect, it does not 
eliminate the risk of NEC: approximately half of the infants who develop severe NEC had been fed 
exclusively with human milk prior to onset [5]. Due to the immature sucking ability of preterm infants 
and challenges in sustained maternal lactation, more than 85% of extremely preterm infants require 
supplementary feeding. 
 
Although pasteurized donor human milk (pDHM) is widely used as a supplement, its clinical 
efficacy and safety compared to preterm formula (PTF) remain uncertain. Meta-analyses suggest 
that when used as a sole or supplemental feeding source, pDHM may help reduce the incidence 
of NEC [6]. However, these studies are often limited by small sample sizes and low methodological 
quality, and many include only NEC cases treated with antibiotics, which are prone to diagnostic 
bias. More importantly, no current studies have demonstrated that pDHM reduces mortality or the 
incidence of invasive infections. Furthermore, several studies have shown that infants fed with 
pDHM have slower head circumference growth and weight gain [7]. Also, there is recent evidence 
that pDHM use may result in adverse developmental outcomes[8-10]. 
 
 
 

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To compensate for the nutritional inadequacies of donor milk—particularly its relatively low and 
variable protein and energy content—many neonatal intensive care units (NICUs) routinely add 
multi-component bovine-derived human milk fortifiers. However, the use of fortifiers remains 
controversial: some clinicians are concerned that the bovine proteins they contain may increase 
the risk of NEC, while others worry that not adding fortifiers will fail to meet the nutritional 
requirements of preterm infants [11-13]. Additionally, there is concern that routine macronutrient 
fortification will expose some babies to excessively high protein intakes that are damaging to 
neurodevelopment [14]. 
The current evidence base is still limited. Systematic reviews indicate that routine fortifier use 
does not clearly reduce NEC incidence or improve long-term neurodevelopmental outcomes, 
though it may offer some short-term benefits in growth. 
 
This study aims to fill these critical evidence gaps through a real-world, stratified, nested, 
double-randomized trial. The trial will compare: (1) the effects of pDHM and PTF as supplemental 
feeding options when maternal milk is insufficient; and (2) the outcomes of routine versus non-
routine use of nutritional fortifiers. Conducted across multiple neonatal units in China, the study will 
include preterm infants born at less than 29 weeks’ gestational age. By evaluating the impact of 
these commonly used feeding strategies on NEC, mortality, growth, and neurodevelopmental 
outcomes, the study seeks to provide robust evidence to inform clinical practice, reduce variations 
in feeding approaches, and improve health outcomes for preterm infants. 
 
II. Study Objectives 
Primary Objectives:   
To evaluate the survival without surgery-requiring necrotizing enterocolitis (NEC) at 34 weeks 
corrected gestational age in preterm infants born at less than 29 weeks of gestation when donor 
pasteurized human milk (pHDM), or preterm formula (PTF) is used to supplement own mother’s 
milk (OMM) when it is insufficient. 
To assess whether routine use of human milk fortifiers (HMF), added to human milk (including both 
OMM and pHDM), is beneficial for this population of preterm infants. 

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Secondary Objectives:   
To evaluate the effects of supplementing OMM with pHDM, or PTF on language and cognitive 
development as well as other outcomes at 2 years of age in preterm infants born at less than 29 
weeks of gestation. 
 
III. Study Methods 
This study is a high-efficiency, nationwide, real-world data-based, multicenter, dual randomization, 
open-label randomized controlled trial (RCT), embedded within routine clinical care. 
The study includes two randomizations: Babies may participate in either or both randomizations. 
First randomization (occur when the attending clinician decides a supplemental feed is required 
because the volume of Own Mother’s Milk is insufficient): We will compare the benefits of 
supplementing with pHDM versus preterm formula (1:1) in cases of insufficient breast milk supply. 
When randomly assigned to the preterm infant formula group, if it was confirmed that milk protein 
allergy could be treated with hydrolyzed formula [15]. 
 
Second randomization (when receiving 60-120 ml/kg of human milk ): We will evaluate the 
differences and benefits between routine fortification and selective fortification, which is only 
considered when the infant meets predefined criteria for growth faltering (Preterm infants exhibit a 
sustained decline in growth velocity for weight, length, or head circumference, demonstrated by a 
downward crossing of centiles on growth curves, despite tolerating and consuming at least 180 
mL/kg/day of breast milk or formula. Blood urea levels in these infants remain consistently below 
1.5 mmol/L, and there are no severe complications such as active sepsis or the need for vasoactive 
medications to maintain circulatory stability. Chronic sodium depletion has also been ruled out, as 
this condition alone can lead to growth failure. Additionally, preterm infants are unable to tolerate 
high-volume feeding of 180 mL/kg/day due to specific reasons, such as severe gastroesophageal 
reflux or the presence of a high-output stoma following surgical procedures.) (1:1). 
Randomization will be carried out electronically using an on-line system managed by the Data 
Services Team. 

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Sample Size 
Based on institutional data from 2024, the proportion of preterm infants born at <29 weeks 
gestation who survived to 34 weeks corrected gestational age without requiring surgical 
intervention for necrotizing enterocolitis (NEC) was 66.3%. To detect an absolute improvement to 
73% in this primary outcome with the use of pasteurized donor human milk (pHDM) compared to 
preterm formula (PTF), the group sample sizes of 736 in group 1 and 736 in group 2 achieve 80.038% 
power to detect a difference between the group proportions of -0.0670. The proportion in group 1 
(the treatment group) is assumed to be 0.7300 under the null hypothesis and 0.6630 under the 
alternative hypothesis. The proportion in group 2 (the control group) is 0.7300. The test statistic 
used is the two-sided Z-Test with unpooled variance. The significance level of the test is 0.0500. 
Under these assumptions, a total of 1,472 infants (736 per group) is required. For the second 
randomization we target the same minimally clinically important difference of 0.067. we assume 
50% co-enrolled into both randomizations. We need a total of 2208. Further accounting for potential 
loss to follow-up and missing data (5%), we propose increasing the total sample size to 
approximately 2324 infants.  
 
IV. Study Population 
This study intends to include infants with a gestational age as follows: 
1. Inclusion Criteria (All of the following must be met):   
- Gestational age at birth less than 29 weeks;   
- No contraindications to enteral feeding;   
- Mother is willing to breastfeed.   
 
2. Exclusion Criteria (Any of the following will result in exclusion):   
- For Randomization Group 1: If the infant has already received pasteurized human donor milk 
(pHDM), preterm formula (PTF), or nutritional fortifiers;   
- For Randomization Group 2: If the infant is exclusively fed with preterm formula and the mother 
has no intention to express breast milk;   

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3. Withdrawal Criteria   
Subjects may voluntarily withdraw from the study at any time for any reason. In addition, the subject 
will be withdrawn from the study if any of the following occur:   
(1) The subject experiences a serious adverse event (SAE) during the study, and the investigator 
determines that continued participation poses an unacceptable risk;   
(2) The subject’s condition deteriorates and requires emergency treatment that is inconsistent with 
the study protocol;   
(3) The subject is found to not meet the inclusion criteria or to meet the exclusion criteria after 
enrollment;   
(4) The monitor or ethics committee recommends termination of the subject’s participation;   
(5) The legal guardian withdraws informed consent or explicitly states unwillingness to continue 
participation.   
 
4. Termination Criteria   
Study termination refers to the complete discontinuation of the clinical trial before its planned 
completion:   
(1) A major safety issue arises during the study, requiring immediate termination;   
(2) A critical flaw in the study protocol is discovered, or significant deviations occur, making it difficult 
to evaluate the intervention's effects;   
(3) The sponsor requests to terminate the study. 
 
V. Study Procedures 
1. Identification and Recruitment of Participants   
After preterm infants are admitted to the neonatal unit, a member of the clinical care team (a 
neonatologist or nurse with appropriate training and experience) will assess their eligibility. Preterm 
infants with a gestational age of less than 29 weeks who meet the inclusion criteria will be 
considered for enrollment.   
Informed consent must be obtained from all participants for the following:   

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- Randomization Group 1   
- Randomization Group 2   
- Inclusion of the PARCA-R assessment results at 2 years of age in the preterm infant database   
 
2. Randomization and Timing   
Participants may be enrolled in either one or both of the randomizations. 
Randomization 1 (First week, pHDM vs. PTF, 1:1) will occur when the clinician determines that 
supplemental feeding is required due to insufficient breast milk supply. 
 
Randomization 2 (Second week) will be conducted when the total daily intake of human milk 
(including own mother’s milk [OMM] and/or pHDM) reaches between 60–120 mL/kg.   
- Randomization will be to either routine fortification or no routine fortification in a 1:1 ratio.   
- The term “no routine fortification” is used because “rescue fortification” remains allowed if deemed 
necessary.   
 
3. Follow-up   
No additional study-specific follow-up visits are scheduled.   
Cognitive and language development outcomes at 2 years of age will be collected using the digital 
version of the PARCA-R assessment tool, which is conducted as part of routine clinical care. 
 
Study Flow Diagram 
 
 
VI. Outcome Measures 
Primary Outcome:   

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- Survival to 34 weeks corrected gestational age without surgical necrotizing enterocolitis (NEC) 
 
Secondary Outcomes: 
Assessed at 34 weeks gestational age:   
- NEC requiring surgical intervention   
Assessed at 28 days after birth:   
- Survival   
Assessed at discharge from the neonatal unit:   
- Survival   
- Medically treated NEC   
- Treated retinopathy of prematurity (ROP)   
- Hearing impairment   
- Severe brain injury   
- Length of hospital stay   
- Number of episodes of bloodstream infection   
- Number of days of antibiotic treatment   
- Number of days on parenteral nutrition   
- Number of days of NPO   
- Growth parameters (weight, length, head circumference)   
- Breastfeeding status (exclusive breastfeeding and any breastfeeding)   
 
Assessed at 2 years corrected age:   
- Survival without moderate to severe cognitive or language impairment 
- Growth parameters (weight, length and head circumference) 
 
VII. Risk Prevention and Management 
This study involves preterm infants with a gestational age of less than 29 weeks—a high-risk 
population. Feeding methods and nutritional interventions during the study may impact their health. 
To ensure the highest level of participant safety, the research team has established a 

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comprehensive risk prevention and management protocol. 
Firstly, strict inclusion and exclusion criteria are set to ensure that only infants with a stable 
baseline condition are enrolled. All feeding strategies are based on current standard clinical 
practices and will be implemented through standardized procedures to ensure the safety and 
controllability of the interventions. 
An adverse event monitoring system will be established, and an independent Data and Safety 
Monitoring Board (DSMB) will be set up to independently assess serious adverse events (SAEs) 
and regularly review safety data. If serious adverse events occur during the study (such as 
progression of NEC, infections, or death), they will be promptly reported to the ethics committee 
and relevant regulatory authorities. The need to discontinue individual participation or the entire 
study will be evaluated accordingly.  
The study has clearly defined withdrawal and termination mechanisms, which include, but are 
not limited to: clinical deterioration, use of prohibited interventions, or withdrawal of consent by 
guardians. These provisions ensure that infants receive optimal clinical care under all 
circumstances. 
Regarding data protection, all participant information will be coded, and data collection, 
transmission, and storage will be encrypted. Access will be strictly controlled to prevent breaches 
of personal privacy. The informed consent process will be strengthened. Trained research staff will 
communicate thoroughly with the infant’s guardians, using clear and understandable language to 
explain the study’s purpose, procedures, potential risks, and benefits. Sufficient time will be given 
to allow for an informed decision. During the study, guardians may ask questions at any time or 
choose to withdraw their child from the study. In such cases, the infant will continue to receive 
standard medical care, and their rights and interests will not be affected. 
 
VIII. Adverse Event Recording and Reporting 
During the study, investigators will closely monitor preterm infants for potential adverse events 
(AEs) that may occur during feeding, with particular attention to complications potentially related to 
feeding methods, such as abdominal distension, necrotizing enterocolitis (NEC), feeding 
intolerance, infections, and metabolic disturbances. 

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In the event of an adverse event (including significant adverse events), investigators must 
promptly analyze the cause, assess the severity and its potential relationship to the study 
intervention, and thoroughly document the event. Documentation should include the time of 
occurrence, clinical manifestations, severity, duration, interventions taken, and final outcome. All 
relevant medical information and laboratory test results must be accurately recorded in both the 
original medical records and the study case report forms. 
If a Serious Adverse Event (SAE) occurs—such as NEC requiring surgical intervention, severe 
infection, or death—the investigator must immediately initiate appropriate clinical management, 
prioritizing the infant’s safety. Additionally, a “Serious Adverse Event Report Form” must be 
completed within 24 hours of the event and submitted to the principal investigator and the ethics 
committee. All SAEs will be continuously followed up until the infant’s condition stabilizes, recovers, 
or results in death. Each SAE will be independently reviewed by the Data and Safety Monitoring 
Board (DSMB), which may recommend suspension or termination of the study if necessary. 
 
IX. Data Management 
Completion of Case Report Forms (CRFs): The CRFs will be completed by clinical 
investigators. 
Data Entry and Modification: Data entry and management will be handled by Xu Yanping. The 
REDCap database will be used for data entry and management. To ensure data accuracy, dual 
data entry and cross-verification will be performed independently by two data managers. 
Database Locking: Once the database has been confirmed to be accurate, it will be locked by 
the principal investigator and the statistical analysis team. 
 
X. Statistical Analysis Methods 
This study is a multicenter, double-randomized, open-label real-world randomized controlled 
trial. It primarily evaluates the effects of using pDHM, or PTF for supplemental feeding in the case 
of insufficient maternal breast milk, as well as the routine addition of nutritional fortifiers, on survival 
without surgical NEC by corrected gestational age of 34 weeks and other outcomes in extremely 
preterm infants (gestational age <29 weeks). 

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1. Data Handling and Overall Analytical Strategy   
All statistical analyses will be conducted based on the Intention-to-Treat (ITT) principle, with Per-
Protocol (PP) analysis conducted as a sensitivity analysis. Primary and key secondary outcomes 
will be analyzed using stratified analysis for the dual-randomization design, taking into account the 
independent and interaction effects of the two interventions. Center effects will be included in the 
model as fixed or random effects. 
2. Descriptive Statistics   
- Continuous variables: Will be presented as mean ± standard deviation (SD) or median 
(interquartile range), and compared using t-tests or Wilcoxon rank-sum tests depending on 
distribution.   
- Categorical variables: Will be presented as frequencies and percentages, and compared between 
groups using the χ² test or Fisher’s exact test. 
3. Primary Outcome Analysis   
The primary outcome is the proportion of infants who survive to 34 weeks corrected gestational 
age without requiring surgery for NEC, a binary variable. Between-group comparisons will be 
conducted using a log-binomial regression model or Poisson regression model with robust standard 
errors to estimate relative risk (RR) and 95% confidence intervals, adjusting for confounders such 
as center, birth weight, and gestational age. If substantial center effects are observed, a 
Generalized Linear Mixed Model (GLMM) will be used for analysis. 
4. Secondary Outcome Analysis   
- Binary outcomes (e.g., NEC incidence, mortality, infections, ROP): Will be analyzed using χ² tests 
or logistic regression.   
- Continuous outcomes (e.g., weight, head circumference, length of hospital stay): Will be analyzed 
using ANOVA or linear regression models, with log transformation applied if necessary.   
- Time-to-event outcomes (e.g., time to first NEC, time to discharge): Will be analyzed using Kaplan-
Meier survival analysis and log-rank tests, with further adjustment using Cox proportional hazards 
models. 
5. Missing Data Handling   
For the primary outcome, missing data will be handled using Multiple Imputation, and sensitivity 

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analyses will be performed to assess the impact on results. Reasons for withdrawal or loss to 
follow-up will be recorded, and follow-up will be pursued as far as possible. 
6. Significance Level and Software   
All statistical tests will be two-sided with a significance level of α=0.05. Analyses will be conducted 
using R or SPSS statistical software. 
 
XI Publication Forms of Research Achievements 
Upon completion of the study, the research team will prepare manuscripts based on the collected 
data and submit them for publication in high-impact national and international journals. The 
publications will cover the primary outcomes, subgroup analyses, monitoring of adverse events, 
and long-term follow-up results. In addition, the research findings will be presented and shared at 
national and international academic conferences in the fields of pediatrics and neonatology, in order 
to enhance the academic impact of the study. 
If the study receives funding support, a final report will be submitted as required by the funding 
agency. Moreover, the results will serve as an important reference for enteral feeding strategies in 
preterm infants and are expected to contribute to the development of relevant clinical guidelines or 
expert consensus. 
Where ethically permissible, the research data will be made available for international sharing 
and may be used for further analyses in future studies. 
 
XII Ethical Considerations 
1. Risks and Benefits  
This study is a comparative investigation of feeding strategies based on routine clinical practice. 
The interventions involved—such as donor human milk, preterm infant formula, and nutritional 
fortifiers—are all standard nutritional support methods widely used in current neonatal care, and 
are generally considered low risk. Potential risks during the study include common complications 
associated with preterm infant feeding, such as feeding intolerance, infection, and progression of 
NEC. However, these risks are manageable within the existing medical system and monitoring 
mechanisms, and clear contingency plans are in place. 

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The research team will closely monitor the health status of all participants and promptly 
address any adverse events to ensure maximum safety for the infants. While individual participants 
may not directly benefit from this study, the systematic evaluation of different feeding strategies on 
both short- and long-term outcomes in extremely preterm infants will provide critical evidence for 
optimizing nutritional support. This has the potential to offer safer and more effective feeding 
approaches for future preterm infants, ultimately improving overall health outcomes. Therefore, 
participation in this study is of great significance for the advancement of neonatal medicine. 
 
2. Protection of Participant Privacy   
Only researchers directly involved in this study will have access to participants’ personal 
medical records. All such personnel are bound by confidentiality agreements or investigator 
declarations that include confidentiality clauses. Ethics committees and regulatory authorities are 
permitted to review clinical trial records. During data processing, anonymization techniques will be 
used to remove personally identifiable information. The publication of research findings will not 
disclose any personal information of the participants. All medical records will be securely stored in 
the archives of the Children’s Hospital, Zhejiang University School of Medicine, which follows strict 
data security and confidentiality protocols. 
 
3. Informed Consent and Signing of Consent Forms   
Prior to the initiation of the clinical study, investigators must provide the legal guardians of 
participants with detailed information about the study, including its nature, objectives, potential 
benefits and risks, to ensure full understanding. The study can only begin after the legal guardian 
has signed the informed consent form. 
Each participant’s contact information, including address and phone number, will be recorded 
in detail. Likewise, the physician will provide their own contact information to ensure that the 
participant’s family can reach the research team at any time. 
 
 
 

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References 
1. 
Roberts, A.G., N. Younge, and R.G. Greenberg, Neonatal Necrotizing Enterocolitis: An Update 
on Pathophysiology, Treatment, and Prevention. Paediatr Drugs, 2024. 26(3): p. 259-275. 
2. 
Kong, X., et al., Neonatal mortality and morbidity among infants between 24 to 31 complete 
weeks: a multicenter survey in China from 2013 to 2014. BMC Pediatr, 2016. 16(1): p. 174. 
3. 
Blencowe, H., et al., National, regional, and worldwide estimates of preterm birth rates in the 
year 2010 with time trends since 1990 for selected countries: a systematic analysis and 
implications. Lancet, 2012. 379(9832): p. 2162-72. 
4. 
Qian, T., et al., Necrotizing enterocolitis in low birth weight infants in China: Mortality risk 
factors expressed by birth weight categories. Pediatr Neonatol, 2017. 58(6): p. 509-515. 
5. 
Battersby, C., et al., Incidence and enteral feed antecedents of severe neonatal necrotising 
enterocolitis across neonatal networks in England, 2012-13: a whole-population surveillance 
study. Lancet Gastroenterol Hepatol, 2017. 2(1): p. 43-51. 
6. 
Quigley, M., N.D. Embleton, and W. McGuire, Formula versus donor breast milk for feeding 
preterm or low birth weight infants. Cochrane Database Syst Rev, 2019. 7(7): p. CD002971. 
7. 
Colaizy, T.T., et al., Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor 
Milk or Preterm Infant Formula: A Randomized Clinical Trial. JAMA, 2024. 331(7): p. 582-
591. 
8. 
Bando, N., et al., Association of Enteral Feed Type with Neurodevelopmental and Neonatal 
Outcomes among Infants Born Preterm. J Pediatr, 2025. 281: p. 114536. 
9. 
Chehrazi, M., et al., Outcomes in very preterm infants receiving an exclusive human milk diet, 
or their own mother's milk supplemented with preterm formula. Early Hum Dev, 2023. 187: p. 
105880. 
10. 
O'Connor, D.L., et al., Effect of Supplemental Donor Human Milk Compared With Preterm 
Formula on Neurodevelopment of Very Low-Birth-Weight Infants at 18 Months: A Randomized 
Clinical Trial. JAMA, 2016. 316(18): p. 1897-1905. 
11. 
Thanigainathan, S. and T. Abiramalatha, Early fortification of human milk versus late 
fortification to promote growth in preterm infants. Cochrane Database Syst Rev, 2020. 7(7): p. 
CD013392. 

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12. 
Gao, C., et al., Comparison of different protein concentrations of human milk fortifier for 
promoting growth and neurological development in preterm infants. Cochrane Database Syst 
Rev, 2020. 11(11): p. CD007090. 
13. 
Brown, J.V., et al., Multi-nutrient fortification of human milk for preterm infants. Cochrane 
Database Syst Rev, 2016(5): p. CD000343. 
14. 
Das, S., et al., High protein intake on later outcomes in preterm children: a systematic review 
and meta-analysis. Pediatr Res, 2025. 97(1): p. 67-80. 
15.   Rigourd V, et al. Indications for extensively hydrolyzed cow's milk protein in the neonatal period. 
Arch Pediatr. 2024;31(6):353-6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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The Effects of Different Enteral Feeding Regimens on Necrotizing 
Enterocolitis, Mortality, and Neurodevelopment in Very Preterm 
Infants: A Multicenter Double-Randomized Trial 
 
 
 
 
 
 
 
 
 
Informed Consent Form 
Nov. 26, 2025 
 
 
 
 
 
 
 
 

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Dear Parent or Legal Guardian, 
Your child is invited to participate in a research study entitled:” The Effects of Different Enteral 
Feeding Regimens on Necrotizing Enterocolitis, Mortality, and Neurodevelopment in Very Preterm 
Infants: A Multicenter Double-Randomized Trial." 
 
Participation in this study is entirely voluntary. This informed consent document provides important 
information about the study. Please read it carefully before deciding whether your child will 
participate. If you have any questions or do not understand any part of this document, please ask 
the study doctor. The research team will answer all of your questions. 
 
This study is being conducted at the Neonatal Intensive Care Unit (NICU) of the Children’s Hospital, 
Zhejiang University School of Medicine, by Dr. Zheng Chen and his team. The study has been 
reviewed and approved by the Medical Ethics Committee of the Children’s Hospital, Zhejiang 
University School of Medicine. 
 
1. Why is this study being conducted? 
Extremely preterm infants have immature gastrointestinal function and are prone to various 
complications during feeding. One of the most serious and potentially life-threatening conditions is 
necrotizing enterocolitis (NEC). Currently, mother’s milk is considered the most suitable source of 
nutrition for preterm infants. However, when mother’s milk is insufficient, it remains unclear whether 
donated human milk or preterm formula should be used as a supplement, and whether nutritional 
fortifiers should be added. 
 
This study aims to evaluate how different enteral feeding strategies affect health outcomes in 

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extremely preterm infants, including the incidence of NEC, mortality, growth, and 
neurodevelopmental outcomes at 2 years of age. Through this research, we hope to identify safer 
and more effective feeding strategies for preterm infants to improve their survival and 
developmental outcomes. 
 
2. What needs to be done before participating in the study? 
If you and your child decide to participate, you will first be asked to sign this informed consent form 
before any study-related activities begin. If a new version of the consent form is developed during 
the study, you will be asked to sign it again. 
 
3. How will the study be conducted? 
This is a multicenter study involving several hospitals, aiming to recruit a total of 2,324 participants. 
Each center will enroll patients competitively. Our hospital aims to recruit at least 200–300 
participants. 
 
After signing this consent form, your child will undergo screening. The screening visit involves the 
following: Gestational age less than 29 weeks; No contraindications to enteral feeding; The mother 
is willing to express breast milk. 
In addition, to avoid interference, infants who have already received donor milk, preterm formula, 
or human milk fortifier, or who have been exclusively fed with preterm formula and whose mothers 
are not willing to express breast milk, will be excluded from the study. 
 
After screening, the study doctor will determine if your child is eligible to continue in the study. If 
your child is not eligible, the doctor will explain the reasons and discuss alternative treatment 
options with you. 
The total duration of your child’s participation in the study will be approximately 24 months. 
 
Your child’s participation will include the following: 
1) Participant Identification and Recruitment 

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After admission to the neonatal unit, a trained and experienced member of the clinical care team 
(either a neonatologist or a nurse) will assess your child’s eligibility. 
All participants must provide informed consent for the following: 
Randomization 1 
Randomization 2 
Inclusion of the 2-year cognitive and language development assessment (PARCA-R) results in the 
preterm infant database 
 
2) Randomization and Timeline 
Your child may take part in one or both randomizations: 
When the attending doctor determines that supplemental feeding is necessary due to insufficient 
mother’s milk, Randomization 1 will be conducted: Donor human milk vs. Preterm formula (1:1 
ratio). 
When the total daily intake of human milk (including mother’s milk and/or donor milk) reaches 
between 60–120 ml/kg, Randomization 2 will be conducted: Routine fortification vs. No routine 
fortification (1:1 ratio). 
The term “no routine fortification” means that rescue fortification is still allowed when clinically 
necessary. 
 
3) Follow-Up 
No additional study visits are scheduled beyond routine care. At 2 years of age, your child’s 
cognitive and language development will be assessed using the digital PARCA-R questionnaire, 
which is conducted as part of routine clinical care. 
 
4. Are there any discomforts or risks in participating in this study? Are there protective 
measures in place? 
This study involves extremely preterm infants with a gestational age of less than 29 weeks, who 
are considered a high-risk population. However, the feeding strategies used in this study are all 
standard clinical practices and are not expected to negatively impact your child’s health. 

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To ensure the utmost safety of participants, the research team has implemented thorough risk 
prevention measures. First, strict inclusion and exclusion criteria have been established to ensure 
that only infants in stable condition are enrolled. All feeding protocols are based on current clinical 
practices and will be carried out following standardized procedures to guarantee the safety and 
controllability of interventions. 
 
In terms of information protection, all participant data will be coded and managed using encrypted 
data collection, transmission, and storage systems, with strict access control to prevent personal 
information leaks. The informed consent process will be strengthened by having trained research 
personnel communicate fully with the child’s guardians. They will explain the study’s purpose, 
procedures, potential risks and benefits in clear and understandable language, and allow sufficient 
time for decision-making. 
 
During the study, guardians may ask questions at any time or choose to withdraw from the study. 
If you choose to withdraw, your child will continue to receive standard medical care, and their rights 
and interests will not be affected. This study only collects clinical data and information and does 
not involve any changes to routine diagnostic or treatment procedures, and therefore poses no 
additional medical risk to participants. 
 
5. What are the benefits of participating in this study? 
Your child may not receive direct medical benefits from participating in this study, as all feeding 
methods used are already part of standard clinical care. The purpose of the study is to compare 
their effectiveness and safety. 
 
However, the information gathered will help doctors and researchers better understand the impact 
of different feeding methods on preterm infants, particularly in preventing NEC, reducing mortality, 
and supporting neurodevelopment. The results of this study may provide a more scientific basis for 
feeding strategies in future cases of preterm infants, potentially benefiting many babies in the future. 

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Thus, while your child may not benefit directly, their participation is of great significance to the 
advancement of neonatal medicine. 
 
6. Are there other treatment options besides participating in this study? 
Yes. If you choose not to participate, your child will still receive standard neonatal care and feeding 
management at the hospital. This includes the use of mother’s milk, donor milk, preterm formula, 
and nutritional fortifiers, depending on the child’s individual needs. 
 
The feeding and nutritional interventions used in this study are all based on current clinical practices, 
and the only difference is that they are assigned randomly for the purpose of scientific evaluation. 
Participation is entirely voluntary, and not participating will not affect the quality of medical care 
your child receives. 
 
7. What happens if my child is harmed by participating in this study? 
All feeding methods and nutritional interventions used in this study are standard in clinical practice, 
and all medical care will be conducted following established guidelines. Therefore, the risk of 
research-related harm is very low. 
 
However, if any physical harm related to the study does occur, the research team will take 
immediate and appropriate medical action to ensure your child receives prompt and proper 
treatment. The hospital will evaluate the situation according to national and hospital policies and 
may provide medical assistance or compensation as appropriate. 
 
Your child’s safety is always the top priority of this study. If any serious adverse events occur, the 
research team will report them promptly to the ethics committee and, if necessary, stop the 
intervention to protect your child’s best interests. 
 
Even if you have signed this informed consent form, you still retain all your legal rights. 

22 
 
 
8. Are there any costs associated with participating in this study? 
There are no additional costs for participating in this study. You will only need to pay for routine 
hospitalization and medical care as usual. 
 
9. Will I receive any compensation for participating in this study? 
There will be no financial compensation or reimbursement provided for participation in this study. 
 
10. Is participation in this study mandatory? Can we withdraw after joining? 
No, participation in this study is completely voluntary. You have the right to refuse to allow your 
child to participate. 
You may also withdraw your child from the study at any time during the research process. 
Withdrawing from the study will not result in any fines, discrimination, or retaliation, and it will not 
affect your child's future medical care or rights. 
If you wish to withdraw your child from the study, please inform us. We will ensure that your child 
exits the study in the safest possible manner. 
 
11. Under what circumstances may my child be withdrawn from the study? 
The study physician has the right to withdraw your child from the study if any of the following 
situations occur:  
You or your child do not follow the instructions provided by the study team, showing poor 
compliance; 
The study physician believes that continued participation would cause unnecessary harm; 
The study is terminated by the Ethics Committee or a regulatory authority. 
 
12. What happens if new information about this study becomes available? 
During the course of the study, if new information arises that may affect your child's willingness to 
continue participation, the study physician will inform you and your child in a timely manner. You 
will be given sufficient time to consider whether you wish to continue in the study. 

23 
 
After the study ends, relevant assessment results will be shared with you and your child. 
 
13. If my child participates in this study, will his/her information be protected? 
All documents related to your child’s participation in the study will be coded for confidentiality. Any 
public reports or publications resulting from this study will not disclose any personal information 
about you or your child. 
All data and associated codes will be securely stored by the researcher's institution. Study data will 
be retained for at least 10 years. 
The study records may be reviewed by the researchers, the Medical Ethics Committee of the 
Children's Hospital, Zhejiang University School of Medicine, and government regulatory authorities. 
 
14. Who should I contact if I have questions about the study? 
You may ask questions about any aspect of the study that you do not understand. The study team 
will answer all your questions. If you feel your questions have not been fully answered or the 
explanations are unclear, you are encouraged to continue asking questions until you are satisfied. 
Contact information is as follows: 
 
Chen Zheng, Phone: 13857151000 
Xu Yanping, Phone: 13685757726 
If you have any concerns regarding your child’s rights as a research participant or if you would like 
to report any dissatisfaction or concerns about the study, you may contact the Ethics Committee: 
 
Name: Medical Ethics Committee of the Children’s Hospital, Zhejiang University School of Medicine 
Address: No. 3333 Binsheng Road, Binjiang District, Hangzhou, Zhejiang Province 
Phone: 0571-86670076 
 
 
 
 

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Informed Consent Signature Page 
 
I have read and understood the information in this informed consent form. I have asked 
questions and am satisfied with the answers provided by the study physician. I have been given 
sufficient time and opportunity to inquire about the details of the study and to consider 
whether to allow my child to participate. 
 
I voluntarily agree to allow my child to participate in this study. 
 
Signing this informed consent form does not mean I give up any of my legal rights. 
 
I have been informed that I will receive a signed copy of this document. 
 
I authorize study personnel, the ethics committee, and government regulatory authorities to 
review my child's medical records. 
 
I  Agree /  Disagree that my child's data from this study may be used in another research. 
 
Participant’s Name (Print): ______________________   
Guardian’s Name (Print): _______________________         
Relationship to Participant: __________________   
Guardian’s Signature: __________________________   
Date and Time of Signature: _____________________         
Contact Phone Number: __________________   
 
(Only one guardian's signature is required for this study) 

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Statement of Person Obtaining Informed Consent: 
 
I confirm that I have explained the details of this study to the participant’s guardian, including 
their rights and the possible benefits and risks. I have answered the guardian’s questions and 
provided them with a signed copy of the informed consent form. 
 
Name of Person Obtaining Consent (Print): __________________   
Signature of Person Obtaining Consent: _____________________   
Date and Time of Signature: _____________________________      
Contact Phone Number: __________________   
 
Impartial Witness Statement (if applicable): 
 
I confirm that the study doctor accurately explained the contents of the informed consent form 
to the participant’s guardian, and that a discussion was held with the guardian. The guardian 
was given the opportunity to ask questions and voluntarily agreed to allow their child to 
participate in the study. 
 
Impartial Witness Name (Print): __________________________   
Impartial Witness Signature: _____________________________   
Date and Time of Signature: _____________________________      
Contact Phone Number: __________________   
 
(An impartial witness signature is required if the participant or their guardian is illiterate.)