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. 2025 Oct 7;25:782. doi: 10.1186/s12887-025-06159-6

Milk temperature reducing necrotizing enterocolitis in very preterm infants: study protocol for a randomized controlled trial

Xuexiu Liu 1, Yuan Shi 1, Fang Li 2, Long Chen 2,✉
PMCID: PMC12502513  PMID: 41057798

Abstract

Background

Necrotizing enterocolitis (NEC) is a common and serious gastrointestinal condition among preterm infants. Factors such as infection, inflammation, and improper feeding are believed to contribute to its onset, but its precise pathophysiology remains unclear. Cold exposure, including feeding at low temperatures, has been associated with increased risks of NEC, yet the direct relationship between feeding temperature and NEC development remains underexplored. This study aims to assess the impact of thermostatic versus standard feeding on the incidence of stage 2 or higher NEC in very preterm infants.

Methods

This randomized controlled trial involves preterm infants (< 32 weeks gestational age) admitted to a neonatal intensive care unit. Participants are randomly assigned to receive either thermostatic feeding, with milk maintained at a set temperature throughout feeding, or standard feeding, where milk is allowed to reach room temperature. Both breast milk and formula are used based on clinical guidelines. Primary outcomes include the incidence of ≥ stage 2 NEC, while secondary outcomes involve the incidence of bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP) > 2nd stages, intraventricular hemorrhage (IVH) > 2nd grades, time to achieve total gastrointestinal nutrition, weekly weight growth, frequency of feeding intolerance, extrauterine growth restriction, and late-onset sepsis.

Expected results

The study expects to identify a significant reduction in NEC incidence among infants receiving thermostatic feeding compared to those in the standard feeding group. Additionally, improvements in feeding tolerance, weekly weight growth, and time to achieve full gastrointestinal nutrition are anticipated.

Conclusion

This study aims to clarify the relationship between feeding temperature and NEC risk, potentially influencing future neonatal care guidelines. By identifying optimal feeding practices, this trial aims to reduce the morbidity and mortality associated with NEC in very preterm infants.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12887-025-06159-6.

Keywords: Milk temperature, Necrotizing enterocolitis, Very preterm infants, Thermostatic feeding, Thermal stress, Protocol, Randomized controlled trial

Background

Necrotizing enterocolitis (NEC) is one of the most common and severe gastrointestinal emergency during the neonatal period [1]. Patients with NEC often present with abdominal distention, vomiting, bloody stool, and typical intestinal wall pneumatosison abdominal radiography [2]. NEC occurs in 5–12% of newborns and is common in preterm and low-birth-weight babies, with a long hospitalization time and high mortality [3–8]. A multicentre study in China Showed that the mortality of NEC was 41.7% among low-birth-weight babies and 50.2% among very-low-birth-weight babies [9]. Despite years of effort, the mortality associated with NEC remains high, up to 30% [10, 11], and surgical intervention is required in 50% of NEC cases [12]; if the patients survive, many may face other troublesome conditions, such as peritonitis, intestinal obstruction, and physical and mental delays [13, 14]. The exact pathophysiological mechanism of NEC is still unclear. Pathophysiologically, impeded blood circulation of the intestinal mucosa may play a pivotal role, resulting in intestinal ischaemia or necrosis. It is currently believed that NEC is caused by multiple factors, including infection, inflammation, prematurity, hypoxic-ischemic events, and improper feeding practices [15].

Regarding treatment for NEC, mainstream clinical strategies are still supportive care for symptoms, including fasting, gastrointestinal decompression, fluid infusion, and anti-infection. Long-term fasting and gastrointestinal decompression can lead to slow milk consumption and long-term enteral nutrition shortage. It seriously affects the nutritional status of infants. Emerging evidence implicates gut dysbiosis and immature vascular supply in NEC pathogenesis. Preterm infants exhibit delayed colonization of beneficial microbiota, predisposing to small intestinal bacterial overgrowth and ileocecal reflux. Concurrently, the circumferential vascular architecture of the gut creates watershed zones vulnerable to ischemic injury during thermal stress [16, 17]. The current mainstream feeding practice for preterm infants involves the use of cold milk. However, feeding cold milk through the digestive tract can expose preterm infants to cold stress. Studies have found that cold exposure can increase levels of enterogenic inflammatory cytokines [18], leading to vascular inflammation [19, 20], increased intestinal permeability [21], and impaired intestinal barrier integrity [22–24]. Animal studies have similarly confirmed that cold feeding can increase intestinal permeability, intestinal inflammatory responses, and immune dysregulation, potentially increasing the susceptibility to NEC [25, 26]. Additionally, a study by Lyu confirmed that hypothermia (cold exposure) at the time of admission is associated with an increased incidence of NEC [27]. Therefore, does the occurrence of NEC relate to cold feeding, and can thermostatic feeding reduce the incidence of NEC? To date, no studies have systematically evaluated the association between feeding temperature during hospitalization and NEC in very preterm infants (VPIs). This prospective clinical trial aims to investigate whether thermostatic feeding can reduce the incidence of stage 2 or higher NEC in this high-risk population, thereby providing the first systematic evidence on the potential benefits of thermostatic feeding in preventing NEC.

Methods

Participants and grouping

This single-center, prospective clinical trial was registered in the Chinese clinical trial registry, registration number: ChiCTR2100044805, (the registration date: 27/03/2021). The trial will be performed in accordance with the prospective trial flow (Fig. 1). Following the approval of the Ethics Committee of the Children’s Hospital of Chongqing Medical University (CHCMU) (No. 2021-70).

Fig. 1.

Fig. 1

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The flow chart of included very preterm infants

Inclusion criteria:

  1. Less than 32 weeks’ gestational age (GA).

  2. Initiation of enteral nutrition within 24 h after birth.

Exclusion criteria:

  1. Parental refusal to participate.

  2. Major congenital anomalies.

  3. Requirement for surgical intervention before randomization.

Study termination criteria:

  1. Death.

  2. Parental decision to withdraw.

  3. Discharge based on medical advice with completed outpatient follow-up within three months after birth.

Data from participants who withdraw from the study will be included in the analysis up to the point of withdrawal, following the intention-to-treat principle.

Randomization

The included VPIs will be randomized and assigned either to the thermostatic feeding or standard feeding groups with a 1:1 ratio, when VPIs fulfil all inclusion criteria. Simple randomization will be done according to a computer-generated random number table and will be posted in a specific secured website available on 24 h/7 days. Infants randomized to one group cannot crossover to the other or vice-versa during the study period.

Blinding

The operators and caregivers will not be blinded, and the outcome assessors and data analysts will be blinded to the intervention.

Study intervention

Once the inclusion criteria are met, milk pumping will begin according to group assignment. Thermostatic feeding group: Breast milk or formula will be administered via an infusion pump (8713030CN, Shenzhen Shengnuo Medical Equipment Co., Ltd., Shenzhen, Guangdong, China) placed in the incubator. The commencing milk temperature will be set at 38℃ [28]; then the milk temperature will naturally drop to reach the same temperature as the incubator, finally being kept thermostatic until the end of feeding (Fig. 2). The setting and adjustment of the incubator temperature will be shown in Table 1 [29]. Standard feeding group: Milk will be delivered using the same infusion pump placed on a stand outside the incubator. The temperature of breast milk or formula will initially be set at 38℃ and cools to the ambient NICU temperature. All pumps will be calibrated to ensure accurate temperature control. Milk temperature will be continuously monitored using a digital thermometer placed at the delivery point. For details on the two feeding methods will be shown in Table 2.

Fig. 2.

Fig. 2

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Milk temperature loss through the tube

Table 1.

The setting and adjustment of temperature of incubator in preterm infants (°C)

Gestational age (weeks) Weeks after birth
1 2 3 4 5 6 7
25+0−25+6 38.0 37.7 37.5 37.2 36.9 36.6 36.3
26+0−26+6 37.7 37.4 37.1 36.8 36.6 36.3 36.0
27+0−27+6 37.3 37.1 36.8 36.5 36.2 35.9 35.7
28+0−28+6 37.0 36.7 36.4 36.2 35.9 35.6 35.3
29+0−29+6 36.7 36.4 36.1 35.8 35.5 35.3 35.0
30+0−30+6 36.3 36.0 35.8 35.5 35.2 34.9 34.6
31+0−31+6 36.0 35.7 35.4 35.1 34.9 34.6 34.3
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Table 2.

Feeding method comparison

Feeding method Thermostatic feeding Standard feeding
Initial temperature 38℃ 38℃
Temperature maintenance method Placed in the incubator, naturally cools to the incubator temperature Placed on the infusion stand, naturally cools to NICU air temperature(24–26℃)
Monitoring method Calibrated digital thermometer Calibrated digital thermometer
Intervention duration Starts within 24 h after birth, continues until discharge or total enteral nutrition is achieved Starts within 24 h after birth, continues until discharge or total enteral nutrition is achieved
Feeding frequency Every 2 h, each feeding lasts 30 min to 2 h Every 2 h, each feeding lasts 30 min to 2 h
Milk volume increase rate Starting at 10 ml/kg/day, gradually increasing based on tolerance Starting at 10 ml/kg/day, gradually increasing based on tolerance
Human milk fortifier Applicable for preterm infants weighing ≤ 1800 g and reaching 50 ml/kg/day, gradually increased to full-strength fortifier Applicable for preterm infants weighing ≤ 1800 g and reaching 50 ml/kg/day, gradually increased to full-strength fortifier
Milk volume increase rate Starting at 10 ml/kg/day, gradually increasing based on tolerance Starting at 10 ml/kg/day, gradually increasing based on tolerance
Temperature control equipment Infusion pump model 8713030CN by Shenzhen Shengnuo Medical EquipmentCo.,Ltd., placed in the incubator Infusion pump model 8713030CN by Shenzhen Shengnuo Medical EquipmentCo.,Ltd., placed on the infusion stand
Feeding termination criteria Gradually transition to oral feeding, each feeding lasts 30 min with no feeding intolerance symptoms Gradually transition to oral feeding, each feeding lasts 30 min with no feeding intolerance symptoms
Breast milk processing Pasteurization if breast milk IgG is positive Pasteurization if breast milk IgG is positive
Clinical monitoring Primary and secondary outcome measures Primary and secondary outcome measures
Discharge criteria Weight reaches 1800 g, and no feeding intolerance or other Weight reaches 1800 g, and no feeding intolerance or other
Study termination conditions

1.Death; 2.Parents decide to withdraw;

3.Discharge recommended by doctors, and complete outpatient follow-up within 3 months after birth

1.Death; 2.Parents decide to withdraw;

3.Discharge recommended by doctors, and complete outpatient follow-up within 3 months after birth
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In our study, all VPIs will be started on enteral nutrition within 24 h after birth, utilizing breast milk and/or formula. All enrolled infants will receive human milk (mother’s own milk) as the primary nutrition source. Formula will be used only if human milk is unavailable, with detailed documentation of formula usage for post hoc subgroup analysis [30]. In this study, donor milk was not utilized due to institutional unavailability. Enrolled infants received mother’s own milk as the sole human milk source. Milk handling procedures adhere to the WHO guidelines for safe enteral feeding in preterm infants, with strict temperature monitoring and aseptic techniques. If the IgG of cytomegalovirus in the breast milk is positive, breast milk will be pasteurized. The initial feeding volume will be 10 ml/kg/day, administered once every 2 h, for a duration of 30 min to 2 h each time. If the feeding duration exceeds 30 min, milk will be supplemented every 30 min to prevent fat separation from breast milk or formula; Feeding adding speed: 15–30 ml/kg/d; Target feeding volume: 150 ml/kg/d, according to the clinical application guidelines for neonatal nutrition support in China [31]. Human milk fortifiers (HMF) will be used according to the Chinese Expert Consensus on the Use of Breast Milk Fortifiers in Premature Infants. Bacterial Safety: Milk samples will be tested weekly for bacterial growth using standardized cultures. Feeds exceeding safe bacterial thresholds will be discarded.

Primary and secondary outcomes

The primary outcome of this study was the incidence of ≥ 2nd stage NEC, defined as modified Bell stage 2 or greater based on established Chinese criteria, with additional ultrasound findings included [32]. Secondary outcomes include: Incidence of bronchopulmonary dysplasia (BPD) [33] (based on NICHD 2001 and 2019 definitions). Additional secondary outcomes encompass the incidence of BPD, retinopathy of prematurity (ROP) [34] > 2nd stages, intraventricular hemorrhage (IVH) [35] > 2nd grades, time to full gastrointestinal nutrition, weekly weight growth, frequency of feeding intolerance (FI) [36], extrauterine growth restriction (EUGR) [37], and late-onset sepsis. Cerebral ultrasound will be performed within 72 h of birth and repeated weekly until normalization or discharge. All routine therapies follow Chinese guidelines.

Measurement of milk temperature

During the first week after birth, two identical infusion setups will be prepared per infant—one for actual feeding and the other for temperature measurement. The temperature will be assessed at the time milk is delivered into the stomach and will be measured using the last 1 ml of milk from the second pump, representing the final feeding temperature.

Sample size

The sample size estimation was calculated by PASS software (2008 v8.0.3). Based on prior study [38], average 5.0% of preterm neonates < 32 weeks were diagnosed with ≥ 2nd of NEC. An expected between-group difference was 10% (3% in the thermostatic feeding group and 13% in the standard feeding group), with 90% power and a 2-sided significance level of 0.05, 100 neonates would be needed at least in each group. The incidence of ≥ 2nd of NEC in the thermostatic feeding group and the standard feeding group is expected to be around 5.0% (6/121) and 14.0% (17/121) respectively. The coincidence rate in both groups will be 9.5% (23/242), with 90% power and a 2-sided significance level of 0.05, 111 neonates would be needed at least in each group. Considering a 10% dropout rate of the sample size, during the study period, a total of 242 preterm infants will be enrolled and will complete the trials.

Statistical analysis

Data will be analyzed using SPSS 29.0 software (Chicago, IL, USA). Quantitative variables were first checked for normality using the Kolmogorov-Smirnov test; these variables are presented as the mean ± standard deviation and were compared using two-tailed Student’s T-tests/one-way ANOVA. Quantitative data are described by frequencies, composition ratios, and percentages. Pearson’s χ2 test, Mann-Whitney U test, and Fisher’s exact test were used to compare the two groups. Comparisons between different groups were performed using the Friedman test. For all analyses, P < 0.05 was regarded as significant.

Data monitoring board

An independent data monitoring committee belonging to the Central Ethics Committee of Children’s Hospital of Chongqing Medical University has been established for the trial. The board will advise the principal investigator (YS) who will remain the only responsible for the trial conduction and for any eventual decision to stop or continue it.

Expected results

  1. Reduction in NEC incidence: Thermostatic feeding is expected to reduce the incidence of stage 2 or higher NEC compared to standard feeding practices in very preterm infants. This benefit may be attributed to reduced thermal stress on the gastrointestinal tract and enhanced intestinal integrity.

  2. Improved gastrointestinal outcomes: Thermostatic feeding may accelerate the time to achieve full gastrointestinal nutrition, which could also be reflected in faster weight gain and a lower incidence of feeding intolerance.

  3. Reduction in secondary complications: A decrease in secondary complications such as BPD, ROP > 2nd stages, and IVH > 2nd grades is expected, as these conditions are often linked to systemic inflammation and poor overall neonatal outcomes.

  4. Better nutritional status: With more stable and controlled feeding temperatures, very preterm infants are expected to demonstrate improved nutritional uptake, reflected in greater weekly weight gain and enhanced overall development.

Discussion

The correlation between feeding temperature and NEC in neonates is a subject of significant interest and continuous investigation. NEC remains a prevalent and severe gastrointestinal emergency in the preterm infant, with considerable morbidity and mortality rates [35, 39]. While the precise mechanisms underlying NEC development are not fully elucidated, factor such as feeding practice is believed to contribute [40–42]. Since Silverman et al. [43] firstly reported that maintaining body temperature by regulating thermal environment during the first 5 days after birth significantly reduced death rate in preterm neonates, many studies have already demonstrated that admission hypothermia is related to the increased incidence of NEC [11, 16, 27]. Research on the association between feeding temperature and NEC risk has produced mixed results. Some studies, including Neu et al., [44] suggest that low feeding temperatures may heighten NEC risk, possibly due to thermal stress on preterm infants’ delicate gastrointestinal mucosa. Epidemiological observations and clinical studies offer valuable insights into safe feeding practices in neonatal care. Thermal stress may exacerbate intestinal ischemia by triggering vasoconstriction in watershed areas, while thermostatic feeding could mitigate this by preserving mucosal perfusion. Furthermore, temperature modulation may stabilize the gut microbiome, reducing dysbiosis-driven inflammation. These studies stress the importance of feeding temperature to minimize thermal stress on the infant’s gastrointestinal tract and mitigate NEC risk. But no studies reported the associations between thermostatic feeding during hospitalization and NEC. Our study provides new insight into interpreting the etiology of NEC, representing the first investigation to compare the effects of thermostatic feeding and standard feeding on NEC in VPIs.

Research exploring the relationship between feeding temperature and the risk of NEC risk has yielded inconsistent results. Some studies suggest that low feeding temperatures might increase NEC risk, emphasizing the critical role of optimal feeding temperature in reducing thermal stress on the infant’s gastrointestinal tract and mitigating NEC risk. However, to date, no study has specifically assessed the impact of thermostatic feeding during hospitalization on the development of NEC. Our study seeks to fill this gap by providing novel insights into the etiology of NEC. It represents the first investigation to directly compare the effects of thermostatic versus standard feeding on the incidence of NEC in extremely preterm infants.

This study is a protocol, with data to be collected during the trial’s future implementation. The primary goal of this paper is to outline the study design and methodology, providing a solid foundation for future research. The anticipated outcomes of this project are expected to significantly advance the understanding and management of NEC in VPIs through the thermostatic feeding.

However, this study has limitations due to its single-center design, which may affect the generalizability of the findings. Furthermore, potential confounding factors, such as variations in clinical practices and caregiver adherence to feeding protocols, could influence the results. Thirdly, the absence of donor milk in our cohort may limit the generalizability of findings to settings where donor milk is used. Future multicenter studies incorporating donor milk are warranted to validate our results.

In conclusion, while the precise relationship between feeding temperature and NEC risk requires further clarification, integrating evidence-based recommendations into neonatal care protocols can optimize feeding practices and reduce the incidence and severity of NEC in vulnerable VPIs. Further research is needed to better understand the specific mechanisms by which feeding temperature influences NEC pathogenesis and refine clinical guidelines accordingly.

Supplementary Information

Supplementary Material 1. (104.6KB, doc)

Acknowledgements

The authors would like to thank the participants of this study.

Declaration of interests

No financial disclosure, and the other authors also have no financial disclosures relevant to this article. No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the individuals of this article.

Open access

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/.

Authors’ contributions

Dr L.X.X contributed to collection of data, drafted the initial manuscript and reviewed the manuscript, Dr S.Y reviewed the manuscript, Dr L.F contributed to methodology, formal analysis, and reviewed the manuscript, Dr C.L conceptualized and designed the study, funding acquisition, critically reviewed the manuscript for important intellectual content. All authors revised the manuscript and approved the final manuscript as submitted.

Funding

The study was funded by The Chongqing Science and Health Joint Medical Research Project (2023MSXM017), The Combined Study Program of Health Committee and Bureau of Science and Technology of Chongqing (2022MSXM001), National Key Research and Development Program of China (2022YFC2704801)，Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0257), Science and health key project of Chongqing Health Commission (2023ZDXM024) and The First Research foundation of Young Neonatologist of China International Medical Foundation-New Seeding Initial (Z-2019-41-2101-04).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

The study was approved by the ethics Committee of Children’s Hospital of Chongqing Medical University (No. 2021-70) and performed in accordance with the Declaration of Helsinki. Informed consent was obtained from the parents.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1. (104.6KB, doc)

Data Availability Statement

No datasets were generated or analysed during the current study.

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