Bilirubin Thresholds in Preterm Infants on Neonatal Intensive CarE Units: The B-NICE Trial

NCT07674537 | Not Yet Recruiting DMC

• 2 other identifiers: N3 BNICE Trial NL-011571NL-011571
• Study Type: interventional
• Target: 680
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Neonatal hyperbilirubinemia is highly prevalent in very preterm infants born \<30 weeks. Since 2008, uniform Dutch phototherapy thresholds for preterm infants have been used nationwide, largely based on consensus. Consequently, \>80% of very preterm infants receive phototherapy for several days, accompanied by repeated blood sampling and reduced opportunities for skin-to-skin care. The corresponding UK National Institute for Health and Care Excellence (NICE) guideline applies higher (less strict) thresholds, which may reduce overtreatment, but comparative safety for very preterm infants has not been established in a randomized trial. The investigators hypothesize that using NICE thresholds is non-inferior to Dutch thresholds for survival without neurodevelopmental impairment (NDI) at two years' corrected age, while reducing treatment burden. Objective: Primary: To determine whether initiating phototherapy according to NICE thresholds is non-inferior to Dutch thresholds with regard to survival without NDI at two years' corrected age in infants born \<30 weeks of gestation. Secondary: To compare phototherapy exposure (incidence, duration and cumulative exposure) and monitoring burden (e.g., number of bilirubin blood samples, temperature instability, biomarkers of oxidative stress (subpopulation)), and to evaluate parent-infant outcomes (skin-to-skin contact time, parental stress/satisfaction), and nursing workload (time dedicated to bilirubin-related care). Study design: Nationwide multicenter, parallel-group, open-label randomized non-inferiority trial with 1:1 allocation, stratified by center and gestational age category (\<28 weeks and ≥28 weeks). Follow-up continues to the routine neurodevelopmental assessment at two years' corrected age. Planned project duration: 36 months. Study population: Very preterm infants born \<30+0 weeks of gestation, admitted to a participating Dutch NICU within 24 hours after birth. Intervention: Bilirubin monitoring and phototherapy according to one of two threshold strategies: (1) current Dutch phototherapy thresholds (control) or (2) thresholds from the UK NICE guideline (intervention). Phototherapy is delivered using standard NICU devices. Main study parameters/endpoints: Primary endpoint: survival without NDI at two years' corrected age. NDI is defined as Bayley Scales of Infant and Toddler Development, fourth Edition, Dutch Version (BSID-IV-NL) cognitive and/or motor composite score \<85 and/or hearing impairment and/or visual impairment. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Both strategies reflect accepted standards of care with routine bilirubin monitoring. Incremental burden consists mainly of additional registration (phototherapy use, bilirubin sampling, skin-to-skin contact, temperature instability), parental questionnaires and, in selected centers, collection of stress-related biomarkers from urine, feces, or waste material from routine blood samples to explore the physiological impact of phototherapy. No biobanking for future unspecified research is planned. The investigators will also use routinely collected and stored monitor data to assess sleep (sleep-wake states and sleep fragmentation) in a subset of infants. Neurodevelopmental follow-up at two years corrected age is routine care in Dutch NICUs. Bilirubin levels above thresholds in both groups will be mitigated by routine monitoring and management according to this study protocol. The study is group-related because bilirubin management and potential neurotoxicity thresholds are specific to very preterm infants.

Conditions

Neonatal Hyperbilirubinemia; Treatment Decisions; Neurodevelopmental Outcome; Phototherapy; Exchange Transfusion

Keywords

neonatal jaundice; preterm infants < 30 weeks GA

Outcome Measures

Primary Outcomes (1)

• Survival free NDI.

  NDI is defined as Bayley Scales of Infant and Toddler Development, Fourth Edition, Dutch Version (BSID-IV-NL) cognitive and/or motor composite score \<85 and/or hearing impairment and/or visual impairment.

  Two years' corrected age.

Secondary Outcomes (9)

• Phototherapy Exposure.

  From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.

• Total Serum Bilirubin (TSB).

  From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.

• Number of blood samples for bilirubin quantification.

  From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever cpmes first.

• Parent-infant skin-to-skin contact time.

  Daily, from NICU admission through postnatal day 10.

• Episodes of temperature instability during phototherapy

  Daily, from NICU admission through postnatal day 10.

Study Arms (2)

Dutch phototherapy and exchange thresholds (control)

ACTIVE COMPARATOR

Current phototherapy and exchange thresholds according to the Dutch national guideline, which are lower than the UK (NICE) thresholds after the first days.

Other: Phototherapy; Other: Exchange Transfusion

United Kingdom phototherapy and exchange thresholds (NICE guideline; intervention)

EXPERIMENTAL

Current phototherapy and exchange thresholds according to NICE guideline, which are higher than the Dutch thresholds after the first days.

Other: Phototherapy; Other: Exchange Transfusion

Interventions

Phototherapy OTHER

This study is a nationwide multicenter, parallel-group, open-label randomized non-inferiority trial conducted in Dutch neonatal intensive care units (NICUs) within the Neonatology Network Netherlands (N3). Eligible infants will be randomized 1:1 to bilirubin management using either the current Dutch phototherapy and exchange thresholds (control) or the higher thresholds from the UK NICE guideline (intervention). The trial is open-label because threshold application is embedded in routine clinical decision-making.

Dutch phototherapy and exchange thresholds (control); United Kingdom phototherapy and exchange thresholds (NICE guideline; intervention)

Exchange Transfusion OTHER

This study is a nationwide multicenter, parallel-group, open-label randomized non-inferiority trial conducted in Dutch neonatal intensive care units (NICUs) within the Neonatology Network Netherlands (N3). Eligible infants will be randomized 1:1 to bilirubin management using either the current Dutch phototherapy and exchange thresholds (control) or the higher thresholds from the UK NICE guideline (intervention). The trial is open-label because threshold application is embedded in routine clinical decision-making.

Dutch phototherapy and exchange thresholds (control); United Kingdom phototherapy and exchange thresholds (NICE guideline; intervention)

Eligibility Criteria

• Age: 24 Weeks - 29 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Gestational age at birth \<30+0 weeks.
• Admission to a participating NICU within 24 hours after birth.
• Parental consent according to the approved consent procedure

You may not qualify if:

• Major congenital anomalies, excluding intraventricular hemorrhage, expected to affect survival or neurodevelopmental outcome.
• Antenatal diagnosis of immune hemolytic disease of the fetus or newborn (such as RhD antagonism) requiring protocolized alternative management.

Sponsors & Collaborators

• University Medical Center Groningen: lead
• Isala: collaborator
• Maastricht University Medical Center: collaborator
• Leiden University Medical Center: collaborator
• Maxima Medical Center: collaborator
• UMC Utrecht: collaborator
• Erasmus Medical Center: collaborator
• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): collaborator
• University Medical Center Nijmegen: collaborator

Study Sites (1)

Beatrix Children's Hospital, University Medical Center Groningen

Groningen, Provincie Groningen, 9713GZ, Netherlands

Location

Related Publications (17)

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  PMID: 18971491 BACKGROUND

• Tyson JE, Pedroza C, Langer J, Green C, Morris B, Stevenson D, Van Meurs KP, Oh W, Phelps D, O'Shea M, McDavid GE, Grisby C, Higgins R; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Does aggressive phototherapy increase mortality while decreasing profound impairment among the smallest and sickest newborns? J Perinatol. 2012 Sep;32(9):677-84. doi: 10.1038/jp.2012.64. Epub 2012 May 31.

  PMID: 22652561 BACKGROUND

• Bugaiski-Shaked A, Shany E, Mesner O, Sergienko R, Wainstock T. Association Between Neonatal Phototherapy Exposure and Childhood Neoplasm. J Pediatr. 2022 Jun;245:111-116. doi: 10.1016/j.jpeds.2022.01.046. Epub 2022 Feb 1.

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  PMID: 3969352 BACKGROUND

• Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. J Perinatol. 2012 Sep;32(9):660-4. doi: 10.1038/jp.2012.71. Epub 2012 Jun 7.

  PMID: 22678141 BACKGROUND

• Steiner LA, Bizzarro MJ, Ehrenkranz RA, Gallagher PG. A decline in the frequency of neonatal exchange transfusions and its effect on exchange-related morbidity and mortality. Pediatrics. 2007 Jul;120(1):27-32. doi: 10.1542/peds.2006-2910.

  PMID: 17606558 BACKGROUND

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  PMID: 3881731 BACKGROUND

• Mukherjee D, Coffey M, Maisels MJ. Frequency and duration of phototherapy in preterm infants <35 weeks gestation. J Perinatol. 2018 Sep;38(9):1246-1251. doi: 10.1038/s41372-018-0153-4. Epub 2018 Jun 19.

  PMID: 29915375 BACKGROUND

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  PMID: 29119603 BACKGROUND

• Hulzebos CV, Dijk PH, van Imhoff DE, Bos AF, Lopriore E, Offringa M, Ruiter SA, van Braeckel KN, Krabbe PF, Quik EH, van Toledo-Eppinga L, Nuytemans DH, van Wassenaer-Leemhuis AG, Benders MJ, Korbeeck-van Hof KK, van Lingen RA, Groot Jebbink LJ, Liem D, Mansvelt P, Buijs J, Govaert P, van Vliet I, Mulder TL, Wolfs C, Fetter WP, Laarman C; BARTrial Study Group. The bilirubin albumin ratio in the management of hyperbilirubinemia in preterm infants to improve neurodevelopmental outcome: a randomized controlled trial--BARTrial. PLoS One. 2014 Jun 13;9(6):e99466. doi: 10.1371/journal.pone.0099466. eCollection 2014.

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• Moll M, Goelz R, Naegele T, Wilke M, Poets CF. Are recommended phototherapy thresholds safe enough for extremely low birth weight (ELBW) infants? A report on 2 ELBW infants with kernicterus despite only moderate hyperbilirubinemia. Neonatology. 2011;99(2):90-4. doi: 10.1159/000302719. Epub 2010 Jul 17.

  PMID: 20639681 BACKGROUND

• Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N, De Rijke Y, Sinaasappel M, Barkovich J. Changes in globus pallidus with (pre)term kernicterus. Pediatrics. 2003 Dec;112(6 Pt 1):1256-63. doi: 10.1542/peds.112.6.1256.

  PMID: 14654594 BACKGROUND

• Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed. 2003 Nov;88(6):F455-8. doi: 10.1136/fn.88.6.f455.

  PMID: 14602689 BACKGROUND

MeSH Terms

Conditions

Hyperbilirubinemia, Neonatal; Jaundice, Neonatal

Interventions

Phototherapy; Exchange Transfusion, Whole Blood

Condition Hierarchy (Ancestors)

Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperbilirubinemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Therapeutics; Blood Transfusion; Biological Therapy

Central Study Contacts

Christian V Hulzebos, MD, PhD, Assistent Professor

CONTACT

+31-503612488; c.v.hulzebos@umcg.nl

Peter H Dijk, MD, PhD

CONTACT

+31-503612488; p.h.dijk@umcg.nl

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 11, 2026
• First Posted: June 29, 2026
• Study Start: August 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): November 1, 2029
• Last Updated: June 29, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: From start date until end date.
• Access Criteria: The study will adhere to FAIR (Findable, Accessible, Interoperable, and Reusable) data principles. De-identified individual participant data, study protocol, statistical analysis plan, and supporting documentation will be made available to qualified researchers upon reasonable request and subject to applicable ethical, legal, and data protection requirements. Metadata describing the available datasets will be publicly accessible through an appropriate repository.

Locations

NL (1)