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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
680
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.
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.
Beatrix Children's Hospital, University Medical Center Groningen
Groningen, Provincie Groningen, Netherlands
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.
Time frame: Two years' corrected age.
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.
Time frame: 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.
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.
The number of blood samples for bilirubin quantification recorded in a bedside log.
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.
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.
Time frame: 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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: Postnatal day 10.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.