Clinical Centre Karlsruhe, Franz-Lust Clinic for Paediatrics, Karlsruhe, Germany.
University Hospital Homburg, Saarland University Medical Center, Clinic for Paediatrics and Neonatology, Homburg, Germany.
Lancet Respir Med. 2024 Jul;12(7):544-555. doi: 10.1016/S2213-2600(24)00073-0. Epub 2024 Apr 18.
Vitamin A plays a key role in lung development, but there is no consensus regarding the optimal vitamin A dose and administration route in extremely low birthweight (ELBW) infants. We aimed to assess whether early postnatal additional high-dose fat-soluble enteral vitamin A supplementation versus placebo would lower the rate of moderate or severe bronchopulmonary dysplasia or death in ELBW infants receiving recommended basic enteral vitamin A supplementation.
This prospective, multicentre, randomised, parallel-group, double-blind, placebo-controlled, investigator-initiated phase 3 trial conducted at 29 neonatal intensive care units in Austria and Germany assessed early high-dose enteral vitamin A supplementation (5000 international units [IU]/kg per day) or placebo (peanut oil) for 28 days in ELBW infants. Eligible infants had a birthweight of more than 400 g and less than 1000 g; gestational age at birth of 32 weeks postmenstrual age or younger; and the need for mechanical ventilation, non-invasive respiratory support, or supplemental oxygen within the first 72 h of postnatal age after admission to the neonatal intensive care unit. Participants were randomly assigned by block randomisation with variable block sizes (two and four). All participants received basic vitamin A supplementation (1000 IU/kg per day). The composite primary endpoint was moderate or severe bronchopulmonary dysplasia or death at 36 weeks postmenstrual age, analysed in the intention-to-treat population. This trial was registered with EudraCT, 2013-001998-24.
Between March 2, 2015, and Feb 27, 2022, 3066 infants were screened for eligibility at the participating centres. 915 infants were included and randomly assigned to the high-dose vitamin A group (n=449) or the control group (n=466). Mean gestational age was 26·5 weeks (SD 2·0) and mean birthweight was 765 g (162). Moderate or severe bronchopulmonary dysplasia or death occurred in 171 (38%) of 449 infants in the high-dose vitamin A group versus 178 (38%) of 466 infants in the control group (adjusted odds ratio 0·99, 95% CI 0·73-1·55). The number of participants with at least one adverse event was similar between groups (256 [57%] of 449 in the high-dose vitamin A group and 281 [60%] of 466 in the control group). Serum retinol concentrations at baseline, at the end of intervention, and at 36 weeks postmenstrual age were similar in the two groups.
Early postnatal high-dose fat-soluble enteral vitamin A supplementation in ELBW infants was safe, but did not change the rate of moderate or severe bronchopulmonary dysplasia or death and did not substantially increase serum retinol concentrations.
Deutsche Forschungsgemeinschaft and European Clinical Research Infrastructures Network (ECRIN).
维生素 A 在肺发育中起着关键作用，但极低出生体重（ELBW）婴儿的最佳维生素 A 剂量和给药途径尚未达成共识。我们旨在评估早期给予高剂量脂溶性肠内维生素 A 补充剂与安慰剂相比，是否会降低接受推荐的基本肠内维生素 A 补充剂的 ELBW 婴儿发生中度或重度支气管肺发育不良或死亡的发生率。
本研究是在奥地利和德国的 29 个新生儿重症监护病房进行的一项前瞻性、多中心、随机、平行组、双盲、安慰剂对照、研究者发起的 3 期临床试验，对 ELBW 婴儿进行早期高剂量肠内维生素 A 补充（5000 国际单位[IU]/kg/天）或安慰剂（花生油）治疗 28 天。纳入的婴儿出生体重>400 g 且<1000 g；出生时的胎龄为<32 周；且在入院后 72 小时内需要机械通气、无创呼吸支持或补充氧气。参与者按区组随机分组，区组大小为可变（2 和 4）。所有参与者均接受基础维生素 A 补充（1000 IU/kg/天）。主要复合终点为校正胎龄 36 周时的中度或重度支气管肺发育不良或死亡，采用意向治疗人群进行分析。本试验在 EudraCT 上注册，注册号为 2013-001998-24。
2015 年 3 月 2 日至 2022 年 2 月 27 日，在参与中心对 3066 名婴儿进行了筛选，以评估其纳入资格。915 名婴儿被纳入并随机分配至高剂量维生素 A 组（n=449）或对照组（n=466）。平均胎龄为 26.5 周（SD 2.0），平均出生体重为 765 g（162）。高剂量维生素 A 组 449 名婴儿中有 171 名（38%）发生中度或重度支气管肺发育不良或死亡，对照组 466 名婴儿中有 178 名（38%）（校正比值比 0.99，95%CI 0.73-1.55）。两组中至少发生一次不良事件的参与者人数相似（高剂量维生素 A 组 256 名[57%]，对照组 281 名[60%]）。两组在基线、干预结束时和校正胎龄 36 周时的血清视黄醇浓度相似。
早期给予 ELBW 婴儿高剂量脂溶性肠内维生素 A 补充是安全的，但并未改变中度或重度支气管肺发育不良或死亡的发生率，也未显著增加血清视黄醇浓度。
德国研究联合会和欧洲临床研究基础设施网络（ECRIN）。
