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

June 24, 2026 updated by: University Medical Center Groningen

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

RATIONALE Very preterm infants frequently develop neonatal hyperbilirubinemia due to immature hepatic conjugation and increased red blood cell turnover. When rising bilirubin levels are left untreated, unbound bilirubin can cross the immature blood-brain barrier, potentially causing bilirubin-induced neurologic dysfunction (BIND) and, in severe cases, kernicterus.

Phototherapy is effective in lowering bilirubin concentrations and prevention of exchange transfusions, and is very frequently applied in very preterm infants. However, phototherapy is not without drawbacks. Phototherapy exposure is associated with higher mortality (especially in sick, mechanically ventilated extremely low birth weight infants < 1000 g), and some studies report increased oxidative stress, disturbed thermoregulation, elektrolyte imbalance, cardiovascular and gastrointestinal effects. In addition, exposure to intense light during phototherapy, together with prolonged eye shielding, may affect the development of circadian rhythms and sleep-wake organization. Conflicting data exist on few long-term adverse effects of neonatal phototherapy, such as a modestly increased risk of childhood cancer and seizures. Phototherapy requires frequent blood sampling with risk of anemia and increases nursing workload in already resource-constrained NICUs. Moreover, prolonged phototherapy exposure can reduce opportunities for skin-to-skin care and negatively affect early parent-infant bonding.

When phototherapy fails, escalation of care to an exchange transfusion is indicated, being an invasive procedure with well-known complications.

In the Netherlands, uniform phototherapy and exchange thresholds for preterm infants have been used since 2008. These thresholds are consensus-based, relatively strict and lead to phototherapy in >80% of infants born <32 weeks. International variation is substantial; notably, the UK NICE guideline uses higher thresholds. Given the potential burdens and possible adverse effects of phototherapy, minimizing unnecessary treatment is in the best interest of both the preterm infant and the parents. Yet, there is currently no robust RCT evidence to support any specific threshold strategy in very preterm infants.

The B-NICE trial addresses this evidence gap by comparing Dutch and NICE threshold strategies in a nationwide multicenter randomized non-inferiority design, focusing on long-term safety (survival without neurodevelopmental impairment (NDI) at the corrected age of two years) and short-term reductions in treatment burden, including fewer hours and days of phototherapy, fewer bilirubin measurements and heel pricks, less handling of the infant, and more opportunities for uninterrupted skin-to-skin care and parent-infant bonding. By tailoring phototherapy more closely to the bilirubin level needed to remain below a presumed safe threshold, the study aims to minimize unnecessary exposure to phototherapy and reduce its associated burden and potential adverse effects, while preserving its clinical benefits and maintaining patient safety.

Study Type

Interventional

Enrollment (Estimated)

680

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Christian V Hulzebos, MD, PhD, Assistent Professor
  • Phone Number: +31-503612488
  • Email: c.v.hulzebos@umcg.nl

Study Contact Backup

  • Name: Peter H Dijk, MD, PhD
  • Phone Number: +31-503612488
  • Email: p.h.dijk@umcg.nl

Study Locations

  • Netherlands
    • Provincie Groningen
      • Groningen, Provincie Groningen, Netherlands, 9713GZ
        • Beatrix Children's Hospital, University Medical Center Groningen
        • Contact:
          • Christian V Hulzebos

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Dutch phototherapy and exchange thresholds (control)
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

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.

Other: Exchange Transfusion

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.
Experimental: United Kingdom phototherapy and exchange thresholds (NICE guideline; intervention)
Current phototherapy and exchange thresholds according to NICE guideline, which are higher than the Dutch thresholds after the first days.
Other: Phototherapy

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.

Other: Exchange Transfusion

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Survival free NDI.
Time Frame: 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.
Two years' corrected age.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phototherapy Exposure.
Time Frame: From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
Incidence of phototherapy use, total duration of phototherapy, and cumulative phototherapy exposure during the study period. Phototherapy data will be recorded prospectively in a bedside log and expressed as the proportion of infants receiving phototherapy, number of phototherapy episodes, and cumulative hours of phototherapy per infant.
From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
Total Serum Bilirubin (TSB).
Time Frame: From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
TSB levels (µmol/L) determined by routine laboratory assays and documented in the electronic health record.
From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
Number of blood samples for bilirubin quantification.
Time Frame: From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever cpmes first.
The number of blood samples for bilirubin quantification recorded in a bedside log.
From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever cpmes first.
Parent-infant skin-to-skin contact time.
Time Frame: Daily, from NICU admission through postnatal day 10.
Total duration of parent-infant skin-to-skin contact during the study period, recorded prospectively in a bedside log and expressed as minutes per day and cumulative minutes.
Daily, from NICU admission through postnatal day 10.
Episodes of temperature instability during phototherapy
Time Frame: Daily, from NICU admission through postnatal day 10.
Number of episodes of temperature instability during phototherapy will be recorded from the electronic health record. Temperature instability is defined as a temperature < 36C or 38C.
Daily, from NICU admission through postnatal day 10.
Sleep
Time Frame: Daily, from NICU admission through postnatal day 10.
Neonatal sleep, including percentages sleep-wake states and sleep fragmentation, will be assessed from monitor data (in selected centers).
Daily, from NICU admission through postnatal day 10.
Biomarkers of physiological and oxidative stress.
Time Frame: Daily, from NICU admission through postnatal day 10.
Urine (cortisol, 8-hydroxy-2'-deoxyguanosine (8-OHdG) or feces (F2-isoprostanes, epigenetic stress profiling (DNA methylation markers)) or in leftover blood samples (F2-isoprostanes) in neonates receiving intensive phototherapy (in selected centers).
Daily, from NICU admission through postnatal day 10.
Nursing time dedicated to bilirubin-related care.
Time Frame: Daily, from NICU admission through postnatal day 10.
Total nursing time spent on bilirubin-related care activities during NICU admission, including transcutaneous bilirubin measurements, blood sampling for total serum bilirubin testing, initiation and management of phototherapy, documentation, communication with parents, and other bilirubin-related clinical procedures. Nursing time will be recorded using bedside logs and expressed as minutes per patient per day and cumulatively over the study period.
Daily, from NICU admission through postnatal day 10.
Parental stress
Time Frame: Postnatal day 10.
Parental stress measured using the 26-item Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU). Items are scored on a 5-point Likert scale, and results are expressed as mean total and domain scores ranging from 1 to 5, with higher scores indicating greater stress.
Postnatal day 10.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Medical Center Groningen

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

August 1, 2026

Primary Completion (Estimated)

August 1, 2027

Study Completion (Estimated)

November 1, 2029

Study Registration Dates

First Submitted

June 11, 2026

First Submitted That Met QC Criteria

June 24, 2026

First Posted (Actual)

June 29, 2026

Study Record Updates

Last Update Posted (Actual)

June 29, 2026

Last Update Submitted That Met QC Criteria

June 24, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • N3 BNICE Trial NL-011571
  • NL-011571 (Other Identifier: Overzicht van medisch wetenschappelijk onderzoek in Nederland (OMON))

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Supporting information will be available. And we also adhere to a FAIR policy of data use. A coded data dictionary (a description of the variables, or types of data, collected for each individual) will be provided so that the data can be fully interpreted.

IPD Sharing Time Frame

From start date until end date.

IPD Sharing 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.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Phototherapy

Clinical Trials on Phototherapy

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Mauritius

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe