van der Weijden Bo M, Janssen Sanne W C M, van der Weide Marijke C, Cornelisse-van Vugt Renske J P M, Ten Tusscher Gavin W, Lutterman Claire A M, Kamps Arvid W A, Lorente Flores Carmen M, Hol Jeroen, van Laerhoven Henriëtte, Rijpert Maarten, Oeij Nadia A, Schiering Irene A M, Obermann-Borst Sylvia A, Visser Douwe H, van Leeuwen Lisanne M, Kornelisse René F, van Rossum Annemarie M C, Bijlsma Merijn W, Plötz Frans B, Achten Niek B
Department of Paediatrics, Tergooi MC, Hilversum, the Netherlands.
Department of Paediatrics, Amsterdam UMC, Emma Children's Hospital, Amsterdam, the Netherlands.
EClinicalMedicine. 2025 Aug 12;87:103419. doi: 10.1016/j.eclinm.2025.103419. eCollection 2025 Sep.
Newborns are at risk for early-onset sepsis (EOS), occurring 0.2-2.0 per 1000 live births, and for antibiotic overtreatment: approximately 5-15% receive antibiotics for suspected EOS under conventional guidelines with categorical risk factor assessment. Use of the multivariate neonatal EOS calculator prediction tool can reduce overtreatment, but no trials have been conducted to compare its safety to these categorical guidelines.
Between April 12th, 2022, and March 19th, 2024, we conducted an open-label, two-armed, cluster-randomised controlled trial among newborns born at ≥34 weeks' gestational age with ≥1 EOS risk factor, comparing 10 hospitals randomised 1:1 to EOS calculator use versus categorical guideline use (ClinicalTrials.gov number: NCT05274776). The EOS calculator was slightly adapted for Dutch use. The co-primary non-inferiority outcome assessed safety using four predefined harm criteria (respiratory support, circulatory support, referral to intensive care unit, and culture-confirmed EOS). Non-inferiority was established if the upper limit of the 95% confidence interval (CI) for the relative risk did not exceed 1.5. The co-primary superiority outcome assessed the reduction of participants starting antibiotic therapy for suspected EOS within 24 h postpartum. Secondary endpoints were the duration of antibiotic therapy and the initiation of antibiotic therapy between 24 and 72 h after birth. Intention-to-treat and per-protocol analyses were performed.
1830 newborns (183 per cluster) were included. At least one harm criterion was present in 64 (7.0%) of 915 in the EOS calculator arm and 134 (14.6%) of 915 in the categorical guideline arm (relative risk 0.48; 95% Cl 0.36-0.63). Antibiotics for suspected EOS were started in 66 (7.2%) of 915 in the EOS calculator arm, compared with 243 (26.6%) of 915 in the categorical guideline arm (absolute risk reduction: 19.0%, 95% CI 11.3-26.7). Median duration of antibiotics was longer in the EOS calculator arm (5.5 days, IQR 1.8-6.6) than in the categorical guideline arm (2.1 days, IQR 1.6-6.3) (P 0.0019). We found no difference in the proportion of newborns started on antibiotic therapy for suspected EOS between 24 and 72 h after birth. Adverse event rates were similar between arms. Readmission for suspected early-onset sepsis occurred three times in the EOS calculator and two times in the categorical guideline arm. Any cultures obtained at readmission remained negative, and any symptoms resolved completely.
These trial data support safety and effectiveness of the EOS calculator for harm criteria and for the proportion of participants that started antibiotic therapy.
This study was supported by SPIN, the General Paediatrics Research Network of the Dutch Association for Paediatrics, supported by het Cultuurfonds.
新生儿有早发型败血症（EOS）的风险，发病率为每1000例活产中有0.2 - 2.0例，同时存在抗生素过度治疗的问题：在采用分类风险因素评估的传统指南下，约5% - 15%的疑似EOS新生儿接受了抗生素治疗。使用多变量新生儿EOS计算器预测工具可以减少过度治疗，但尚未进行试验来比较其与这些分类指南的安全性。
在2022年4月12日至2024年3月19日期间，我们在孕周≥34周且有≥1个EOS风险因素的新生儿中进行了一项开放标签、双臂、整群随机对照试验，将10家医院按1:1随机分为使用EOS计算器组和分类指南组（ClinicalTrials.gov编号：NCT05274776）。EOS计算器针对荷兰的使用情况进行了轻微调整。共同主要的非劣效性结局使用四个预定义的不良标准（呼吸支持、循环支持、转诊至重症监护病房和培养确诊的EOS）评估安全性。如果相对风险的95%置信区间（CI）上限不超过1.5，则确定为非劣效。共同主要的优效性结局评估产后24小时内开始接受疑似EOS抗生素治疗的参与者人数的减少情况。次要终点是抗生素治疗的持续时间以及出生后24至72小时内抗生素治疗的开始情况。进行了意向性分析和符合方案分析。
共纳入1830例新生儿（每组183例）。EOS计算器组915例中有64例（7.0%）至少存在一项不良标准，分类指南组915例中有134例（14.6%）（相对风险0.48；95% CI 0.36 - 0.63）。EOS计算器组915例中有66例（7.2%）开始接受疑似EOS的抗生素治疗，分类指南组915例中有243例（26.6%）（绝对风险降低：19.0%，95% CI 11.3 - 26.7）。EOS计算器组抗生素的中位使用时间（5.5天，IQR 1.8 - 6.6）长于分类指南组（2.1天，IQR 1.6 - 6.3）（P = 0.0019）。我们发现出生后24至72小时内开始接受疑似EOS抗生素治疗的新生儿比例没有差异。两组的不良事件发生率相似。疑似早发型败血症的再入院率在EOS计算器组为3次，在分类指南组为2次。再入院时进行的任何培养结果均为阴性，任何症状均完全缓解。
这些试验数据支持了EOS计算器在不良标准以及开始接受抗生素治疗的参与者比例方面的安全性和有效性。
本研究由荷兰儿科学会普通儿科学研究网络SPIN资助，并得到文化基金的支持。
