Bilirubin Thresholds in Preterm Infants on Neonatal Intensive CarE Units: The B-NICE Trial
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 680
- 试验地点
- 1
- 主要终点
- Survival free NDI.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 24 Weeks 至 29 Weeks（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Phototherapy (Other)
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.
干预措施: Exchange Transfusion (Other)
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.
干预措施: Phototherapy (Other)
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.
干预措施: Exchange Transfusion (Other)
结局指标
主要结局
Survival free NDI.
时间窗: 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.
次要结局
- Phototherapy Exposure.(From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.)
- Total Serum Bilirubin (TSB).(From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.)
- Number of blood samples for bilirubin quantification.(From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever cpmes first.)
- Parent-infant skin-to-skin contact time.(Daily, from NICU admission through postnatal day 10.)
- Episodes of temperature instability during phototherapy(Daily, from NICU admission through postnatal day 10.)
- Sleep(Daily, from NICU admission through postnatal day 10.)
- Biomarkers of physiological and oxidative stress.(Daily, from NICU admission through postnatal day 10.)
- Nursing time dedicated to bilirubin-related care.(Daily, from NICU admission through postnatal day 10.)
- Parental stress(Postnatal day 10.)