Supplementary Material for: Risk Factors for Late-Onset Sepsis in Preterm Infants: A Multicenter Case-Control Study

Background: Late-onset sepsis (LOS) in preterm infants is a leading cause of mortality and morbidity. Timely recognition and initiation of antibiotics are important factors for improved outcomes. Identification of risk factors could allow selection of infants at an increased risk for LOS. Objectives: The aim was to identify risk factors for LOS. Methods: In this multicenter case-control study, preterm infants born at ≤30 weeks of gestation were included at 9 neonatal intensive care units. Detailed demographical and clinical data were collected daily up to day 28 postnatally. Clinical and demographic risk factors were identified using univariate and multivariate regression analyses in a 1: 1 matched case-control cohort. Results: In total, 755 infants were included, including 194 LOS cases (41 gram-negative cases, 152 gram-positive cases, and 1 fungus). In the case-control cohort, every additional day of parenteral feeding increased the risk for LOS (adjusted OR = 1.29; 95% CI 1.07–1.55; p = 0.006), whereas antibiotics administration decreased this risk (OR = 0.08; 95% CI 0.01–0.88; p = 0.039). These findings could largely be attributed to specific LOS-causative pathogens, since these predictive factors could be identified for gram-positive, but not for gram-negative, LOS cases. Specifically cephalosporins administration prior to clinical onset was inversely related to coagulase-negative staphylococcus LOS (CoNS-LOS) development. Formula feeding was an independent risk factor for development of CoNS-LOS (OR = 3.779; 95% CI 1.257–11.363; p = 0.018). Conclusion: The length of parenteral feeding was associated with LOS, whereas breastmilk administration was protective against CoNS-LOS. A rapid advancement of enteral feeding, preferably with breastmilk, may proportionally reduce the number of parenteral feeding days and consequently the risk for LOS.背景：早产儿晚发性脓毒症（Late-onset Sepsis, LOS）是导致新生儿死亡与致残的首要病因。及时识别并启动抗菌药物治疗是改善患儿预后的关键环节。识别晚发性脓毒症的危险因素，有助于筛选出发病风险升高的早产儿。 研究目的：本研究旨在明确早产儿晚发性脓毒症的危险因素。 研究方法：本研究为多中心病例对照研究，纳入9家新生儿重症监护病房（Neonatal Intensive Care Unit, NICU）收治的胎龄≤30周的早产儿，于患儿出生后28天内每日收集详细的人口学与临床资料。采用1:1匹配的病例对照队列设计，通过单因素与多因素回归分析，筛选与晚发性脓毒症相关的人口学及临床危险因素。 研究结果：本研究共纳入755例早产儿，其中194例确诊晚发性脓毒症，包括革兰阴性菌感染41例、革兰阳性菌感染152例、真菌感染1例。在该1:1匹配的病例对照队列中，肠外营养持续时间每增加1天，晚发性脓毒症的发病风险即显著升高（校正优势比（Adjusted Odds Ratio, adjusted OR）=1.29，95%置信区间（Confidence Interval, CI）：1.07~1.55，P=0.006）；而抗菌药物的使用可降低该风险（优势比（Odds Ratio, OR）=0.08，95%置信区间：0.01~0.88，P=0.039）。上述关联在很大程度上可归因于特定的晚发性脓毒症致病病原体：该预测因子仅在革兰阳性菌感染的晚发性脓毒症病例中得到验证，而在革兰阴性菌感染病例中未观察到类似关联。具体而言，临床发病前使用头孢菌素类药物，与凝固酶阴性葡萄球菌性晚发性脓毒症（Coagulase-Negative Staphylococcus LOS, CoNS-LOS）的发生呈负相关。配方奶喂养是凝固酶阴性葡萄球菌性晚发性脓毒症的独立危险因素（优势比=3.779，95%置信区间：1.257~11.363，P=0.018）。 研究结论：肠外营养持续时长与晚发性脓毒症的发病风险相关，而母乳喂养对凝固酶阴性葡萄球菌性晚发性脓毒症具有保护作用。尽早推进肠内营养（优先选用母乳喂养）可按比例缩短肠外营养的持续天数，进而降低晚发性脓毒症的发病风险。