Fentanyl Exposure Is Associated with Adverse Respiratory Outcomes in Ventilated Preterm Neonates: A Retrospective Matched Cohort Study

Background/Objectives: Fentanyl is widely used in ventilated preterm neonates, but respiratory safety evidence is limited. We assessed the association between fentanyl exposure during mechanical ventilation and respiratory outcomes in preterm neonates <34 weeks and explored a candidate exposure-duration threshold, defined as the duration of continuous fentanyl infusion beyond which the risk of adverse respiratory outcomes rises sharply. Methods: Single-centre retrospective cohort study at Policlinico Umberto I, Sapienza University, Rome (2015–2022). Fentanyl-exposed neonates were 1:2 matched to unexposed neonates on gestational age and birth-weight z-score. Primary outcome: bronchopulmonary dysplasia at 36 weeks postmenstrual age (multivariable logistic regression); secondary outcome: duration of invasive ventilation. A composite outcome (bronchopulmonary dysplasia or invasive ventilation ≥ 7 days) was used for threshold analysis with restricted cubic splines, maximally selected Wald χ2, and segmented logistic regression. Results: Of 315 eligible neonates, 50 fentanyl-exposed neonates were matched with 92 unexposed neonates (n = 142). Fentanyl exposure was associated, after adjustment for gestational age and fetal distress, with bronchopulmonary dysplasia (adjusted odds ratio 5.49, 95% CI 1.72–17.54) and longer invasive ventilation (adjusted exp(β) 2.25, 95% CI 1.54–3.29). Three complementary threshold methods were consistent with an exploratory signal around 3 days of continuous infusion, beyond which composite-outcome odds rose, although the breakpoint estimate was imprecise. Conclusions: Fentanyl exposure during mechanical ventilation was associated, after adjustment for gestational age and fetal distress, with bronchopulmonary dysplasia and longer invasive ventilation in preterm neonates <34 weeks. A possible signal around 3 days of continuous infusion is proposed as a hypothesis-generating stewardship prompt, not as a decision rule.