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

Overview

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.

Interventions

• 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 clinic
• 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 clinic

Primary outcome measures

• Survival free NDI. [Time frame: Two years' corrected age.]

Secondary outcome measures (9)

• 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.]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• Beatrix Children's Hospital, University Medical Center Groningen — Groningen

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 photot PMID 18971491
• 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 PMID 22652561
• 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. PMID 35120988
• Digitale 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. PMID 34716218
• Auger 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. PMID 30684392
• Hotta 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. PMID 37105535
• Shoris 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. PMID 37892362
• Lipsitz 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. PMID 3969352

Identifiers

NCT: NCT07674537 · N3 BNICE Trial NL-011571 · NL-011571

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗