WithHolding Enteral Feeds Around Blood Transfusion (International)

Necrotizing Enterocolitis Clinical Trial

— WHEAT  

Official title:

The WHEAT International Trial: WithHolding Enteral Feeds Around Red Cell Transfusion to Prevent Necrotizing Enterocolitis in Preterm Neonates: an International, Multi-centre, Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05213806
• Other study ID #: 1027137
• Secondary ID: 1025465
• Status: Recruiting
• Phase: N/A
• Start date: January 28, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: September 2023
• Source: IWK Health Centre
• Contact: Emily MacLeod
• Phone: 9024706679
• Email: emily.macleod[@]iwk.nshealth.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 4333
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Weeks

Eligibility

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; buccal colostrum will not be counted as enteral feeding).

3. Infants where enteral feeding is contraindicated in the first 7 days after birth [e.g. Major congenital abnormality of the gastrointestinal tract (GIT)].

4. Previous episode of NEC or spontaneous intestinal perforation (SIP) prior to first packed cell transfusion.

Related Conditions & MeSH terms

• Enterocolitis
• Enterocolitis, Necrotizing
• Necrotizing Enterocolitis

Intervention

Other:
• 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.
• Continued feeds around transfusion
Continued enteral feeds

Locations

Country	Name	City	State
Canada	IWK Health	Halifax	Nova Scotia

Sponsors (3)

Lead Sponsor	Collaborator
IWK Health Centre	Canadian Institutes of Health Research (CIHR), Imperial College London

Country where clinical trial is conducted

Canada, 

References & Publications (16)

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. Erratum In: JAMA Pediatr. 2017 Jul 1;171(7):712. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Duro D, Kalish LA, Johnston P, Jaksic T, McCarthy M, Martin C, Dunn JC, Brandt M, Nobuhara KK, Sylvester KG, Moss RL, Duggan C. Risk factors for intestinal failure in infants with necrotizing enterocolitis: a Glaser Pediatric Research Network study. J Pediatr. 2010 Aug;157(2):203-208.e1. doi: 10.1016/j.jpeds.2010.02.023. Epub 2010 May 6. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: Transfusion. 2015 Sep;55(9):2295. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2007 May;92(3):F193-8. doi: 10.1136/adc.2006.099929. Epub 2006 Sep 19. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	NEC Stage II	NEC stage II or more after the first transfusion (modified Bell staging criteria) - Clinical signs and symptoms plus pneumatosis or portal/hepatic air diagnosed by x-ray or other imaging techniques	From randomization to 40 weeks postmenstrual age
Secondary	Severe NEC	Histologically or surgically confirmed or recorded on the death certificate. These infants will be identified as described in Battersby et al. which will include infants recorded as being transferred for surgery.	From randomization to 40 weeks postmenstrual age
Secondary	Death	All-cause mortality	From randomization to 40 weeks postmenstrual age
Secondary	Late onset sepsis	Culture positive sepsis, onset after 72 hours of life	From randomization to 40 weeks postmenstrual age
Secondary	Number of days with a central venous line in situ	Number of days with a central venous line in situ	From birth to date of discharge home
Secondary	Number of central line associated bloodstream infections	Includes laboratory-confirmed bloodstream infection and clinical sepsis	From randomization to 40 weeks postmenstrual age
Secondary	Duration of any parenteral nutrition in days	Duration of any parenteral nutrition in days	From birth to 40 weeks postmenstrual age
Secondary	Growth	Weight and head circumference z score.	At date of discharge home
Secondary	Spontaneous Intestinal Perforation	Histologically or surgically confirmed or recorded in the death certificate.	From randomization to 40 weeks postmenstrual age
Secondary	Duration of hospital stay	Total duration of neonatal care in days including all levels of care (intensive care, high dependency care, special care and ordinary care)	From birth to date of discharge home
Secondary	Bronchopulmonary Dysplasia (BPD)/Chronic Lung Disease	Requiring respiratory support at 36 weeks gestation	At 36 weeks postmenstrual age
Secondary	Retinopathy of prematurity (ROP)	ROP requiring treatment	From randomization to 40 weeks postmenstrual age
Secondary	Severe Brain Injury	Intraventricular haemorrhage (IVH) grade 3 or 4 or cystic periventricular leukomalacia (PVL)	At 40 weeks postmenstrual age