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

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.