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.
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
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.
研究の種類
研究の種類
入学 (推定)
入学
段階
段階
- 適用できない
連絡先と場所
研究連絡先
研究連絡先
- 名前：Christian V Hulzebos, MD, PhD, Assistent Professor
- 電話番号：+31-503612488
- メール：c.v.hulzebos@umcg.nl
研究連絡先のバックアップ
- 名前：Peter H Dijk, MD, PhD
- 電話番号：+31-503612488
- メール：p.h.dijk@umcg.nl
研究場所
-
-
Provincie Groningen
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Groningen、Provincie Groningen、オランダ、9713GZ
- Beatrix Children's Hospital, University Medical Center Groningen
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コンタクト：
- Christian V Hulzebos
-
-
参加基準
適格基準
適格基準
就学可能な年齢
- 子
健康ボランティアの受け入れ
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：独身
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
|---|---|
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アクティブコンパレータ：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.
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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. |
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実験的：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.
|
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. |
この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Survival free NDI.
時間枠：Two years' corrected age.
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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.
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Two years' corrected age.
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二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Phototherapy Exposure.
時間枠：From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
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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.
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From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
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Total Serum Bilirubin (TSB).
時間枠：From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
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TSB levels (µmol/L) determined by routine laboratory assays and documented in the electronic health record.
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From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever comes first.
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Number of blood samples for bilirubin quantification.
時間枠：From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever cpmes first.
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The number of blood samples for bilirubin quantification recorded in a bedside log.
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From NICU admission until 32 weeks postmenstrual age or transfer from the NICU, whichever cpmes first.
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Parent-infant skin-to-skin contact time.
時間枠：Daily, from NICU admission through postnatal day 10.
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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.
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Daily, from NICU admission through postnatal day 10.
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Episodes of temperature instability during phototherapy
時間枠：Daily, from NICU admission through postnatal day 10.
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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.
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Daily, from NICU admission through postnatal day 10.
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Sleep
時間枠：Daily, from NICU admission through postnatal day 10.
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Neonatal sleep, including percentages sleep-wake states and sleep fragmentation, will be assessed from monitor data (in selected centers).
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Daily, from NICU admission through postnatal day 10.
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Biomarkers of physiological and oxidative stress.
時間枠：Daily, from NICU admission through postnatal day 10.
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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).
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Daily, from NICU admission through postnatal day 10.
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Nursing time dedicated to bilirubin-related care.
時間枠：Daily, from NICU admission through postnatal day 10.
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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.
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Daily, from NICU admission through postnatal day 10.
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Parental stress
時間枠：Postnatal day 10.
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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.
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Postnatal day 10.
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協力者と研究者
協力者
協力者
出版物と役立つリンク
一般刊行物
- Watchko JF, Maisels MJ. Jaundice in low birthweight infants: pathobiology and outcome. Arch Dis Child Fetal Neonatal Ed. 2003 Nov;88(6):F455-8. doi: 10.1136/fn.88.6.f455.
- 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.
- 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):677-84. doi: 10.1038/jp.2012.64. Epub 2012 May 31.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Maisels 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.
- Steiner 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.
- Brown 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.
- Mukherjee 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.
- Mreihil 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.
- Hulzebos 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.
- Moll 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.
- Govaert P, Lequin M, Swarte R, Robben S, De Coo R, Weisglas-Kuperus N, De Rijke Y, Sinaasappel M, Barkovich J. Changes in globus pallidus with (pre)term kernicterus. Pediatrics. 2003 Dec;112(6 Pt 1):1256-63. doi: 10.1542/peds.112.6.1256.
研究記録日
主要日程の研究
研究開始 (推定)
研究開始
一次修了 (推定)
一次修了
研究の完了 (推定)
研究の完了
試験登録日
最初に提出
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QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (実際)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
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QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
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詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
その他の研究ID番号
- N3 BNICE Trial NL-011571
- NL-011571 (その他の識別子：Overzicht van medisch wetenschappelijk onderzoek in Nederland (OMON))
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
IPD 共有時間枠
IPD 共有アクセス基準
IPD 共有サポート情報タイプ
- STUDY_PROTOCOL
- SAP
- ICF
- ANALYTIC_CODE
- CSR
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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