MANUSCRIPT CITATION

Ojha S, Mitchell E, Johnson M, Gale Christopher, McGuire W, Oddie S, Hall S, Meakin G, Anderson J, P C, Su Y, Johnson S, Walker K, Ogollah R, Mistry H, Naghdi S, Montgomery A, Dorling, J, & Mcintyre J, Hartung R. Full exclusively enteral fluids from day 1 versus gradual feeding in preterm infants (FEED1): a open-label, parallel-group, multicentre, randomised, superiority trial. Lancet Child Adolesc Health 2025; 9:827-36
PMID: 41115446

REVIEWED BY

Johanna Baker and Harsha Gowda
University Hospitals Birmingham
Johanna.baker@nhs.net

CORRESPONDING AUTHOR

Name: Johanna Baker
Email johanna.baker@nhs.net
Telephone 07986285456

TYPE OF INVESTIGATION

Treatment: full enteral feeds versus gradual increase in enteral feeds, a multicentre, randomised controlled trial

QUESTION

In preterm infants between 30+0 and 32+6 weeks gestation (Population), does introducing full enteral feeds from first day of life (intervention) versus gradual increase in enteral feeds (comparison) lead to shorter hospital stay (outcome)?

METHODS

• Design: Multicentre, parallel group, randomised controlled trial in United Kingdom
• Allocation: Mothers allocated randomly using web-based randomisation software with minimization algorithm with random element to ensure balance of key factors
• Blinding: Parents and clinicians non-blinded; investigators and data analysts blinded.
• Follow-up period: 24 months (ongoing)
• Setting: Multicentre randomised controlled trial across 46 neonatal units in UK
• Patients: Preterm infants between 30+0 and 32+6 weeks gestational age within 3 hours of birth who were clinically stable. Infants were excluded if they had a congenital abnormality which made enteral feeding unsafe or were small for gestational age with reversed end diastolic flow on doppler.
• Intervention: Full enteral feeds on first day of life at 60-80ml/kg/day as compared to gradual increase over first days of life with maximum 30ml//kg/day enteral feeds on first day of life with remaining fluids as intravenus fluids or parenteral nutrition.
• Outcomes:
• Primary outcome: Length of Hospital stay
• Secondary outcomes: Survival to discharge, incidence of hypoglycaemia, necrotising enterocolitis, late onset sepsis and rates of breastfeeding at discharge and 6 weeks
• Analysis and Sample Size: A total of 2088 infants were enrolled to the study; 1047 in the full milk feeds group and 1041 in gradual feeding arm
• Patient follow-up: Primary outcome data was missing for 18 infants in each group (due to withdrawal from study or death; 1 record missing in each group), so 98.3% of enrolled infants were included in final analysis.

MAIN RESULTS

2088 infants were enrolled, with a mean gestational age of 31.7 weeks (SD 0.8) and mean birthweight of 1621g (SD 298). Baseline characteristics including sex, birthweight, gestation, birthweight, multiple birth, ethnicity, clinical condition, use of intravenous fluids prior to randomisation (within first 3 hours of birth), method of delivery, and use antenatal steroid and magnesium sulphate were similar across the two groups. In the full milk feeds group, 644 infants (61.5%) received no or less than 24 hours of intravenous fluids or parenteral nutrition from birth; the reason for non-adherence was reported in 387 (27%), and included failure to tolerate enteral feeds, abdominal concerns, hypoglycaemia, and escalation of respiratory support necessitating change in feeds.

The primary outcome studied was length of hospital stay, and results showed no significant difference between the 2 groups, with mean stays of 32.4 days [SD 13.3] and 32.1 days [13.5], with difference of -0.02 days [95% confidence interval -1.07 to 1.03]. Subgroup analysis showed that there remained no significant difference across different gestational ages, or for infants who were small for gestational age.

There was no significant difference noted in any of the safety secondary outcomes studied: survival to discharge (99.6% in both groups with adjusted risk ratio 1.00 [95% CI 0.99 to 1.01]), rates of hypoglycaemia (0.6 and 0.5 in full milk and gradual feeding arms), necrotising enterocolitis (0.4% and 0.6% in full milk and gradual feeding arms respectively, with adjusted risk ratio of 0.67 [95% CI 0.19 to 2.35], microbiologically confirmed or clinically suspected late-onset sepsis, or rates of breastfeeding at discharge or 6 weeks. Infants in the full milk feeds arm reached full enteral feeds quicker, had fewer days of intravenous fluids or parenteral nutrition, and had fewer incidents of peripheral and central access, and all of these outcomes reached statistical significance.

Outcome Full milk feeds group (n=1047) Gradual feeding group (n=1041) Adjusted risk ratio Hazard ratio 95% confidence interval

Survival to discharge 1030/1034 (99.6%) 1027/1031 (99.6%) 1.00 0.99 to 1.01

Necrotising enterocolitis (Bell stage 2 or 3) 4/1030 (0.4%) 6/1027 (0.6%) 0.67 – 0.19 to 2.35

Late onset sepsis 32/1031 (3.1%) 25/1026 (2.4%) 1.27 – 0.76 to 2.13

Any breastfeeding at discharge 447/1026 (43.6%) 434/1021 (42.5%) 1.04 – 0.94 to 1.14

Exclusive breastfeeding at discharge 109/1026 (10.6%) 117/1021 (11.5%) 0.95 – 0.74 to 1.2

Mothers breast milk at 6 weeks 301/697 (43.2%) 276/657 (43.0%) – – –

Number of glucose tests <2.2mmol/L before full enteral feeds (average) 0.6 0.5 – – – Time to full enteral feeds (days) 7.0 (SD 3.5) 7.9 (SD 3.9) – 2.35 1.91 to 2.89 Time with central line until discharge (days) 1.0 (SD 3.4). n= 1029 2.1 (SD 7.0) n= 1022 – -0.87 -1.31 to -0.42 Peripheral cannula until full milk feeding (days) 4.3 (SD 3.0). n=1019 5.3 (SD 2.9) n=1015 – -1.4 -1.29 to -0.78 CONCLUSION This study showed no significant difference in length of hospital stay, survival to discharge, or incidence of hypoglycaemia, necrotising enterocolitis or late-onset sepsis in infants over 30 weeks gestation who were commenced on full enteral milk feeds from the first day of life compared to those who received gradual increase in enteral feeds, but a statistically significant reduction in time taken to reach full enteral feeds, days of intravenous fluids or parenteral nutrition, and incidence of central and peripheral venous access.

COMMENTARY

Much of neonatal care of very preterm infants in the first days of life focuses around advancement of enteral feeding, with a need to balance the advancement of enteral feeds with minimising the risk of associated complications, such as feed intolerance and necrotising enterocolitis (NEC).1 The traditional approach has been one of caution, advocating slow advancement of enteral feeds to mitigate the risk of NEC.2 This cautious approach must be balanced against the need for optimum nutrition, particularly in infants who receive intravenous fluids for the remainder of their fluid volume, and the desire to reduce hospital stay. Adequate nutrition is of vital importance in preterm infants in order to optimise brain development. 3 Additionally, delay in introduction of enteral feeds is associated with problems with functional adaptation of the gastrointestinal tract and disruption in normal gut microbiome. 4

 

Previous smaller randomised controlled trials (RCTs) comparing early full milk feeds to gradual increase suggested that introduction of early full enteral feeds may reduce the length of hospital stay. 5, 6, 7 Of note, 2 of these 3 single-centre RCTs included infants of lower gestational ages, from 28+0 or 29+0 weeks. There was no significant difference in rates of NEC or spontaneous intestinal perforation between these groups, but numbers in this study were low and the studies were underpowered.

 

This current study by Ojha et al is a large, multicentre, randomised controlled study across 46 neonatal units in the United Kingdom. The study was well designed and appropriately powered to answer the primary outcome (length of hospital stay) and other important outcomes for both safety and clinical significance. Randomisation was stratified to ensure that key baseline characteristics were similar across the groups. Whilst it was not possible to blind parents or clinicians, data analysts were blinded to the allocation group. All babies were accounted for, including 1 in each group whose data were lost, and the authors showed >98% follow up of participants to discharge.

 

Contrary to previous studies, this study did not find any reduction in length of hospital stay in the full milk feed arm compared to the gradual feeding arm. However, secondary outcome data for safety parameters including incidence of NEC, late onset sepsis and hypoglycaemia was reassuring. Survival to discharge and breast feeding at discharge were similar in both groups.

 

Therefore, despite showing non-superiority in primary outcome of reduction in length of hospital stay, this study demonstrates that in preterm infants of 30+0 to 32+6 weeks gestation, in the absence of antenatal findings of both small for gestational age and reversed end diastolic flow, it is safe to introduce full enteral feeds from the first day of life. This is important because it justifies a change in clinical practice, and demonstrates that it is safe to commence enteral feeds in infants of this gestation without an initial period of trophic feeds.Introducing full enteral feeds from the first day of life reduces the need for parenteral nutrition or intravenous fluids and confers many advantages, including fewer invasive procedures, improved nutrition for those who would alternatively be receiving intravenous fluids, and reduced costs associated with administration of parenteral nutrition.

 

Future studies focusing on lowering the gestation at birth to 28+0 weeks, in line with the single-centre RCTs,5,7 and faster increment of feeds to achieve full nutritional requirement needs investigation.

REFERENCES

1. Kwok TC, Dorling J, Gale C. Early enteral feeding in preterm infants. Semin Perinatol. 2019; 43(7):151159.
2. Salas, A.A.; Ojha, S. Exclusive enteral nutrition in preterm infants: How early is too early? Semin. Fetal Neonatal Med. 2025; 30:101631.
3. Keunen K, van Elburg RM, van Bel F, Benders MJ. Impact of nutrition on brain development and its neuroprotective implications following preterm birth. Pediatr Res. 2015 Jan;77(1-2):148-55.
4. The SIFT Investigators Group Early enteral feeding strategies for very preterm infants: current evidence from Cochrane reviews Archives of Disease in Childhood – Fetal and Neonatal Edition 2013;98:F470-F472.
5. Razzaghy J, Shukla VV, Gunawan E, Reeves A, Nguyen K, Salas AA. Early and exclusive enteral nutrition in infants born very preterm. Arch Dis Child Fetal Neonatal Ed 2024; 109: 378–83.
6. Alshaikh BN, Hassan O, Alburaki W, et al. Early exclusive enteral feeding in 30–33 weeks gestation infants: a randomized controlled trial. J Perinatol 2025; 45: 628–34
7. Jajoo M, Singh A, Arora N et al. Early total versus gradually advanced enteral nutrition in stable very-low-birth-weight preterm neonates: a randomized, controlled trial Indian J Pediatr. 2022; 89:25-30