Neonatal HyperbilirubinemiaB-NICENCT07674537
Bilirubin Thresholds in Preterm Infants on Neonatal Intensive CarE Units: The B-NICE Trial
A study testing Phototherapy and Exchange Transfusion in people with Neonatal Hyperbilirubinemia and Treatment Decisions, run by University Medical Center Groningen at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 24 to 29 weeks
- Conditions the study is for
- Neonatal Hyperbilirubinemia, Treatment Decisions, Neurodevelopmental Outcome
- What is being tested?
- Phototherapy and Exchange Transfusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 680 participants
- Where
- 1 siteNetherlands
- Study dates
- 1 Aug 2026to 1 Nov 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 24 to 29 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Netherlands1 site
Beatrix Children's Hospital, University Medical Center Groningen
Groningen, Provincie Groningen, 9713GZ
Christian V Hulzebos
About this study
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).
Read more
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.
Read the 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.
- Conditions
- Neonatal Hyperbilirubinemia, Treatment Decisions, Neurodevelopmental Outcome, Phototherapy, Exchange Transfusion
- Being tested
- Phototherapy, Exchange Transfusion
- Keywords
- neonatal jaundice, preterm infants < 30 weeks GA
- Medical subject headings
- Hyperbilirubinemia, Neonatal, Jaundice, Neonatal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PhototherapyOther
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.
Exchange TransfusionOther
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Other: Phototherapy; Other: Exchange Transfusion |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Two years' corrected age.
Secondary outcomes (9)
Phototherapy Exposure.
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.
Measured: From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
Total Serum Bilirubin (TSB).
TSB levels (µmol/L) determined by routine laboratory assays and documented in the electronic health record.
Measured: From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
Number of blood samples for bilirubin quantification.
The number of blood samples for bilirubin quantification recorded in a bedside log.
Measured: From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever cpmes first.
Parent-infant skin-to-skin contact time.
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.
Measured: Daily, from NICU admission through postnatal day 10.
Episodes of temperature instability during phototherapy
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.
Measured: Daily, from NICU admission through postnatal day 10.
Sleep
Neonatal sleep, including percentages sleep-wake states and sleep fragmentation, will be assessed from monitor data (in selected centers).
Measured: Daily, from NICU admission through postnatal day 10.
Biomarkers of physiological and oxidative stress.
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).
Measured: Daily, from NICU admission through postnatal day 10.
Nursing time dedicated to bilirubin-related care.
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.
Measured: Daily, from NICU admission through postnatal day 10.
Parental stress
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.
Measured: Postnatal day 10.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2026
- Study start1 Aug 2026 (estimated)
- Primary completion1 Aug 2027 (estimated)
- Study completion1 Nov 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (17)Papers the sponsor has linked to this study.
- Other trials for Neonatal HyperbilirubinemiaStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 680 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- Isala, Maastricht University Medical Center, Leiden University Medical Center, Maxima Medical Center, UMC Utrecht, Erasmus Medical Center, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), University Medical Center Nijmegen
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07674537
- Sponsor's protocol ID
- N3 BNICE Trial NL-011571
- Other IDs
- NL-011571
- Acronym
- B-NICE
- Status last verified
- Jun 2026
- First submitted
- 11 Jun 2026
- Last updated
- 29 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Publications
Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O'Shea TM, McDavid GE, Perritt RL, Van Meurs KP, Vohr BR, Grisby C, Yao Q, Pedroza C, Das A, Poole WK, Carlo WA, Duara S, Laptook AR, Salhab WA, Shankaran S, Poindexter BB, Fanaroff AA, Walsh MC, Rasmussen MR, Stoll BJ, Cotten CM, Donovan EF, Ehrenkranz RA, Guillet R, Higgins RD; NICHD Neonatal Research Network. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008 Oct 30;359(18):1885-96. doi: 10.1056/NEJMoa0803024.
PubMed 18971491Tyson 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.
PubMed 22652561Bugaiski-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.
PubMed 35120988Digitale JC, Kim MO, Kuzniewicz MW, Newman TB. Update on Phototherapy and Childhood Cancer in a Northern California Cohort. Pediatrics. 2021 Nov;148(5):e2021051033. doi: 10.1542/peds.2021-051033. Epub 2021 Oct 29.
PubMed 34716218Auger N, Laverdiere C, Ayoub A, Lo E, Luu TM. Neonatal phototherapy and future risk of childhood cancer. Int J Cancer. 2019 Oct 15;145(8):2061-2069. doi: 10.1002/ijc.32158. Epub 2019 Feb 8.
PubMed 30684392Hotta M, Ueda K, Ikehara S, Tanigawa K, Nakayama H, Wada K, Kimura T, Ozono K, Sobue T, Iso H; Japan Environment and Children's Study Group. Association between neonatal phototherapy and sleep: The Japan Environment and Children's Study. J Sleep Res. 2023 Oct;32(5):e13911. doi: 10.1111/jsr.13911. Epub 2023 Apr 27.
PubMed 37105535Shoris I, Gover A, Toropine A, Iofe A, Zoabi-Safadi R, Tsuprun S, Riskin A. "Light" on Phototherapy-Complications and Strategies for Shortening Its Duration, A Review of the Literature. Children (Basel). 2023 Oct 17;10(10):1699. doi: 10.3390/children10101699.
PubMed 37892362Lipsitz PJ, Gartner LM, Bryla DA. Neonatal and infant mortality in relation to phototherapy. Pediatrics. 1985 Feb;75(2 Pt 2):422-6. No abstract available.
PubMed 3969352Maisels 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.
PubMed 22678141Steiner 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.
PubMed 17606558Brown AK, Kim MH, Wu PY, Bryla DA. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics. 1985 Feb;75(2 Pt 2):393-400. No abstract available.
PubMed 3881731Mukherjee 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.
PubMed 29915375Mreihil K, Benth JS, Stensvold HJ, Nakstad B, Hansen TWR; Norwegian NICU Phototherapy Study Group; Norwegian Neonatal Network. Phototherapy is commonly used for neonatal jaundice but greater control is needed to avoid toxicity in the most vulnerable infants. Acta Paediatr. 2018 Apr;107(4):611-619. doi: 10.1111/apa.14141. Epub 2017 Dec 4.
PubMed 29119603Hulzebos 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.
PubMed 24927259Moll 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.
PubMed 20639681
Study at a glance
From the registry record, last updated by the sponsor on 29 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Bilirubin Thresholds in Preterm Infants on Neonatal Intensive CarE Units: The B-NICE Trial
- ClinicalTrials.gov ID
- NCT07674537
- Acronym / sponsor ID
- B-NICE / N3 BNICE Trial NL-011571
- Conditions
- Neonatal Hyperbilirubinemia, Treatment Decisions, Neurodevelopmental Outcome, Phototherapy, Exchange Transfusion
- Keywords
- neonatal jaundice, preterm infants < 30 weeks GA
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 680 participants (estimated)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- Isala, Maastricht University Medical Center, Leiden University Medical Center, Maxima Medical Center, UMC Utrecht, Erasmus Medical Center, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), University Medical Center Nijmegen
- Study start
- 1 Aug 2026 (estimated)
- Primary completion
- 1 Aug 2027 (estimated)
- Study completion
- 1 Nov 2029 (estimated)
- First posted
- 29 Jun 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dutch phototherapy and exchange thresholds (control) | Active comparator | Other: Phototherapy, Other: Exchange TransfusionCurrent phototherapy and exchange thresholds according to the Dutch national guideline, which are lower than the UK (NICE) thresholds after the first days. |
| United Kingdom phototherapy and exchange thresholds (NICE guideline; intervention) | Experimental | Other: Phototherapy, Other: Exchange TransfusionCurrent phototherapy and exchange thresholds according to NICE guideline, which are higher than the Dutch thresholds after the first days. |
Who may qualify
- Ages
- 24 to 29 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PhototherapyThis 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 | Dutch phototherapy and exchange thresholds (control), United Kingdom phototherapy and exchange thresholds (NICE guideline; intervention) |
| Exchange TransfusionThis 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 | Dutch phototherapy and exchange thresholds (control), United Kingdom phototherapy and exchange thresholds (NICE guideline; intervention) |
Primary outcome
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.
9 secondary outcomes
Phototherapy Exposure.
Time frame: 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.
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.
Parent-infant skin-to-skin contact time.
Time frame: Daily, from NICU admission through postnatal day 10.
Episodes of temperature instability during phototherapy
Time frame: Daily, from NICU admission through postnatal day 10.
Sleep
Time frame: Daily, from NICU admission through postnatal day 10.
Biomarkers of physiological and oxidative stress.
Time frame: 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.
Parental stress
Time frame: Postnatal day 10.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jun 2026.
- Background: PubMed 18971491Morris BH, Oh W, Tyson JE, Stevenson DK, Phelps DL, O'Shea TM, McDavid GE, Perritt RL, Van Meurs KP, Vohr BR, Grisby C, Yao Q, Pedroza C, Das A, Poole WK, Carlo WA, Duara S, Laptook AR, Salhab WA, Shankaran S, Poindexter BB, Fanaroff AA, Walsh MC, Rasmussen MR, Stoll BJ, Cotten CM, Donovan EF, Ehrenkranz RA, Guillet R, Higgins RD; NICHD Neonatal Research Network. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008 Oct 30;359(18):1885-96. doi: 10.1056/NEJMoa0803024.
- Background: PubMed 22652561Tyson 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.
- Background: PubMed 35120988Bugaiski-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.
- Background: PubMed 34716218Digitale JC, Kim MO, Kuzniewicz MW, Newman TB. Update on Phototherapy and Childhood Cancer in a Northern California Cohort. Pediatrics. 2021 Nov;148(5):e2021051033. doi: 10.1542/peds.2021-051033. Epub 2021 Oct 29.
- Background: PubMed 30684392Auger N, Laverdiere C, Ayoub A, Lo E, Luu TM. Neonatal phototherapy and future risk of childhood cancer. Int J Cancer. 2019 Oct 15;145(8):2061-2069. doi: 10.1002/ijc.32158. Epub 2019 Feb 8.
- Background: PubMed 37105535Hotta M, Ueda K, Ikehara S, Tanigawa K, Nakayama H, Wada K, Kimura T, Ozono K, Sobue T, Iso H; Japan Environment and Children's Study Group. Association between neonatal phototherapy and sleep: The Japan Environment and Children's Study. J Sleep Res. 2023 Oct;32(5):e13911. doi: 10.1111/jsr.13911. Epub 2023 Apr 27.
- Background: PubMed 37892362Shoris I, Gover A, Toropine A, Iofe A, Zoabi-Safadi R, Tsuprun S, Riskin A. "Light" on Phototherapy-Complications and Strategies for Shortening Its Duration, A Review of the Literature. Children (Basel). 2023 Oct 17;10(10):1699. doi: 10.3390/children10101699.
- Background: PubMed 3969352Lipsitz PJ, Gartner LM, Bryla DA. Neonatal and infant mortality in relation to phototherapy. Pediatrics. 1985 Feb;75(2 Pt 2):422-6. No abstract available.
- Background: PubMed 22678141Maisels 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.
- Background: PubMed 17606558Steiner 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.
- Background: PubMed 3881731Brown AK, Kim MH, Wu PY, Bryla DA. Efficacy of phototherapy in prevention and management of neonatal hyperbilirubinemia. Pediatrics. 1985 Feb;75(2 Pt 2):393-400. No abstract available.
- Background: PubMed 29915375Mukherjee 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.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Phototherapy and Exchange Transfusion in people with Neonatal Hyperbilirubinemia and Treatment Decisions, run by University Medical Center Groningen at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 29 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Christian V Hulzebos, MD, PhD, Assistent Professor (+31-503612488, c.v.hulzebos@umcg.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Survival free NDI. (time frame: Two years' corrected age.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07674537, which also lists 17 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jun 2026.