WithHolding Enteral Feeds Around Blood Transfusion (International)

NCT ID: NCT05213806

Last Updated: 2025-11-24

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 4333 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-01-28
• Study Completion Date: 2027-03-31

Brief Summary

The WHEAT International trial is a comparative effectiveness trial exploring whether withholding enteral feeds around the time of blood transfusion in very premature infants (<30 weeks) will reduce the occurrence of Necrotizing Enterocolitis (NEC). Currently both continued feeding and withholding feeding are approved care practices. The current study will randomize infants from Neonatal Intensive Care Units (NICUs) across Canada and the United Kingdom (UK) into one of the two care approaches (withholding or continued feeds) to determine if any significant outcomes are found.

Detailed Description

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating disease that affects mostly the intestine of premature infants. The wall of the intestine is invaded by bacteria, which cause local infection and inflammation that can ultimately destroy the wall of the bowel (intestine). NEC is among the most potentially devastating neonatal diseases and has a mortality of up to 33%, the most severe form (requiring surgery or resulting in death) affects about 5% of infants born at less than 30 gestational weeks; survivors are at high risk of long-term health and developmental problems. Prevention of NEC has been identified as one of the most important research uncertainties in the field of preterm birth. A temporal association between red cell transfusion and the subsequent development of the disease is well described. This 'transfusion-associated NEC' may also be more severe with higher mortality. Very preterm or extremely low birth weight infants are among the most frequently transfused patients: between 56% and 90-95% have at least one transfusion, and those transfused received an average of 5 transfusions in their neonatal stay. Withholding milk feeds during red cell transfusion may reduce the risk of NEC by decreasing postprandial mesenteric ischemia but there may be harmful effects of pausing enteral feeds. However, due to a lack of good quality evidence, there is no consensus regarding the optimal feeding strategy during a blood transfusion.

Both comparator pathways of care are standard practice in Canada and the UK; the WHEAT trial is a comparative effectiveness trial. The two care pathways that will be compared are:

1. Withholding Feeds Around Transfusion: All enteral feeds will be discontinued (the infant will be placed nil by mouth) for 4 hours prior to packed red cell transfusion, during the packed red cell transfusion and until 4 hours post packed red cell transfusion.

2. Continuing Feeds Around Transfusion: Enteral feeds will continue to be given prior, during and after the packed red cell transfusion, in the manner in which they were being given prior to the decision to transfuse.

Infants will remain allocated to the same care pathway until 34(+6) weeks(+days) gestational age.

Conditions

Necrotizing Enterocolitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Withholding feeds around transfusion

All enteral feeds will be discontinued (the infant will be placed nil by mouth) for 4 hours prior to packed red cell transfusion, during the transfusion and until 4 hours post transfusion. During this period, hydration and blood glucose will be maintained according to local practice, commonly by providing parenteral nutrition or intravenous dextrose. Four hours after the red cell transfusion has finished, feeds will be recommenced to how they were being received prior to the decision to transfuse. This duration of withholding feeds will follow the approach used in other trials and observational studies, and identified as the most acceptable in a survey of UK neonatal units. It gives time for milk in the small bowel to transit into the large bowel before the transfusion and for the circulation to stabilize after the transfusion before milk feeds given into the stomach pass through into the small intestine.

Group Type: ACTIVE_COMPARATOR

Withholding feeds around transfusion

Intervention Type: OTHER

Withholding enteral feeds for preterm infants (\<30 weeks) around the time of blood transfusions to determine if any impact on the development and/or severity of Necrotizing Enterocolitis.

Continuing feeds around transfusion

Enteral feeds will continue to be given prior, during and after the packed red cell transfusion, in the manner in which they were being given prior to the decision to transfuse. Infants will remain allocated to the same care pathway until 34(+6) weeks(+days) gestational age.

Group Type: ACTIVE_COMPARATOR

Continued feeds around transfusion

Intervention Type: OTHER

Continued enteral feeds

Interventions

Withholding feeds around transfusion

Withholding enteral feeds for preterm infants (\<30 weeks) around the time of blood transfusions to determine if any impact on the development and/or severity of Necrotizing Enterocolitis.

Intervention Type: OTHER

Continued feeds around transfusion

Continued enteral feeds

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Preterm birth at <30+0 gestational weeks + days

Exclusion Criteria

1. Parent(s) opt-out of trial participation.

2. Packed red cell transfusion with concurrent enteral feeds prior to enrolment. (Infants who have received a packed red cell transfusion while nil-by-mouth are eligible; or minimal enteral nutrition (<15 ml/kg/day feeds) at the time of transfusion; defined as before, during and for at least 4 hours after transfusion, are eligible.

3. Infants who are not being fed at the time of randomization or where enteral feeding is contraindicated [e.g. Major congenital abnormality of the gastrointestinal tract (GIT)].

4. Previous episode of NEC Bell stage 2 or higher or SIP prior to first study packed cell transfusion.

• Maximum Eligible Age: 30 Weeks
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Canadian Institutes of Health Research (CIHR)

OTHER_GOV

Sponsor Role: collaborator

Imperial College London

OTHER

Sponsor Role: collaborator

IWK Health Centre

OTHER

Sponsor Role: lead

Responsible Party

Dr. Balpreet Singh

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Balpreet Singh, MD

Role: PRINCIPAL_INVESTIGATOR

IWK Health, Canada

Jon Dorling, MD

Role: PRINCIPAL_INVESTIGATOR

Princess Anne Hospital, UK

Chris Gale, MD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London, UK

Locations

IWK Health

Halifax, Nova Scotia, Canada

Site Status: RECRUITING

Countries

Canada

Central Contacts

Cari-Lee Carnell

Role: CONTACT

cari-lee.carnell@iwk.nshealth.ca

9024706630

Tara Hatfield

Role: CONTACT

tara.hatfield@iwk.nshealth.ca

9024706630

Facility Contacts

Cari-Lee Carnell

Role: primary

cari-lee.carnell@iwk.nshealth.ca

9024706630

References

Lopez-Reyes JC, Juarez-Campa M. [Integration of teaching, service and research in the health area]. Salud Publica Mex. 1988 Sep-Oct;30(5):714-28. No abstract available. Spanish.

Reference Type: BACKGROUND

PMID: 3217834 (View on PubMed)

Pankov GI, Zarubinskaia LG. [Participation of medical scientists in Don in the revolutionary movement]. Sov Zdravookhr. 1989;(6):61-2. No abstract available. Russian.

Reference Type: BACKGROUND

PMID: 2675329 (View on PubMed)

Duley L, Uhm S, Oliver S; Preterm Birth Priority Setting Partnership Steering Group. Top 15 UK research priorities for preterm birth. Lancet. 2014 Jun 14;383(9934):2041-2042. doi: 10.1016/S0140-6736(14)60989-2. No abstract available.

Reference Type: BACKGROUND

PMID: 24931684 (View on PubMed)

Seges RA, Kenny A, Bird GW, Wingham J, Baals H, Stauffer UG. Pediatric surgical patients with severe anaerobic infection: report of 16 T-antigen positive cases and possible hazards of blood transfusion. J Pediatr Surg. 1981 Dec;16(6):905-10. doi: 10.1016/s0022-3468(81)80844-5.

Reference Type: BACKGROUND

PMID: 6279816 (View on PubMed)

Stritzke AI, Smyth J, Synnes A, Lee SK, Shah PS. Transfusion-associated necrotising enterocolitis in neonates. Arch Dis Child Fetal Neonatal Ed. 2013 Jan;98(1):F10-4. doi: 10.1136/fetalneonatal-2011-301282. Epub 2012 Mar 23.

Reference Type: BACKGROUND

PMID: 22447991 (View on PubMed)

Blau J, Calo JM, Dozor D, Sutton M, Alpan G, La Gamma EF. Transfusion-related acute gut injury: necrotizing enterocolitis in very low birth weight neonates after packed red blood cell transfusion. J Pediatr. 2011 Mar;158(3):403-9. doi: 10.1016/j.jpeds.2010.09.015. Epub 2010 Nov 10.

Reference Type: BACKGROUND

PMID: 21067771 (View on PubMed)

Mally P, Golombek SG, Mishra R, Nigam S, Mohandas K, Depalhma H, LaGamma EF. Association of necrotizing enterocolitis with elective packed red blood cell transfusions in stable, growing, premature neonates. Am J Perinatol. 2006 Nov;23(8):451-8. doi: 10.1055/s-2006-951300. Epub 2006 Sep 28.

Reference Type: BACKGROUND

PMID: 17009195 (View on PubMed)

Cunningham KE, Okolo FC, Baker R, Mollen KP, Good M. Red blood cell transfusion in premature infants leads to worse necrotizing enterocolitis outcomes. J Surg Res. 2017 Jun 1;213:158-165. doi: 10.1016/j.jss.2017.02.029. Epub 2017 Feb 28.

Reference Type: BACKGROUND

PMID: 28601308 (View on PubMed)

Keir AK, Yang J, Harrison A, Pelausa E, Shah PS; Canadian Neonatal Network. Temporal changes in blood product usage in preterm neonates born at less than 30 weeks' gestation in Canada. Transfusion. 2015 Jun;55(6):1340-6. doi: 10.1111/trf.12998. Epub 2015 Feb 5.

Reference Type: BACKGROUND

PMID: 25652740 (View on PubMed)

Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, Peliowski A, Rios A, LaCorte M, Connelly R, Barrington K, Roberts RS. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006 Sep;149(3):301-307. doi: 10.1016/j.jpeds.2006.05.011.

Reference Type: BACKGROUND

PMID: 16939737 (View on PubMed)

Jasani B, Rao S, Patole S. Withholding Feeds and Transfusion-Associated Necrotizing Enterocolitis in Preterm Infants: A Systematic Review. Adv Nutr. 2017 Sep 15;8(5):764-769. doi: 10.3945/an.117.015818. Print 2017 Sep.

Reference Type: BACKGROUND

PMID: 28916576 (View on PubMed)

Sahin S, Gozde Kanmaz Kutman H, Bozkurt O, Yavanoglu Atay F, Emre Canpolat F, Uras N, Suna Oguz S, Underwood MA. Effect of withholding feeds on transfusion-related acute gut injury in preterm infants: a pilot randomized controlled trial. J Matern Fetal Neonatal Med. 2020 Dec;33(24):4139-4144. doi: 10.1080/14767058.2019.1597844. Epub 2019 Mar 28.

Reference Type: BACKGROUND

PMID: 30890001 (View on PubMed)

Neu J. Necrotizing enterocolitis: the search for a unifying pathogenic theory leading to prevention. Pediatr Clin North Am. 1996 Apr;43(2):409-32. doi: 10.1016/s0031-3955(05)70413-2.

Reference Type: BACKGROUND

PMID: 8614608 (View on PubMed)

Battersby C, Longford N, Costeloe K, Modi N; UK Neonatal Collaborative Necrotising Enterocolitis Study Group. Development of a Gestational Age-Specific Case Definition for Neonatal Necrotizing Enterocolitis. JAMA Pediatr. 2017 Mar 1;171(3):256-263. doi: 10.1001/jamapediatrics.2016.3633.

Reference Type: BACKGROUND

PMID: 28046187 (View on PubMed)

Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF, Poole WK, Blakely ML, Wright L, Higgins R; NICHD Neonatal Research Network. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005 Mar;115(3):696-703. doi: 10.1542/peds.2004-0569.

Reference Type: BACKGROUND

PMID: 15741374 (View on PubMed)

Battersby C, Longford N, Mandalia S, Costeloe K, Modi N; UK Neonatal Collaborative Necrotising Enterocolitis (UKNC-NEC) study group. 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 Jan;2(1):43-51. doi: 10.1016/S2468-1253(16)30117-0. Epub 2016 Nov 8.

Reference Type: BACKGROUND

PMID: 28404014 (View on PubMed)

Other Identifiers

1025465

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

1027137

Identifier Type: -

Identifier Source: org_study_id