Cumulative Exposure to Opioids and Benzodiazepines in Extremely Preterm Neonates

Abstract Objective: To quantify opioid and benzodiazepine exposure in extremely preterm neonates and assess variation by gestational age, facility, and clinical factors. Study Design: Cross-sectional study of 1,501 neonates born at 23–28 weeks gestation at Kaiser Permanente Northern California (2011–2021). Medication data were extracted from electronic records. Cumulative opioid and benzodiazepine exposures were standardized to morphine and lorazepam equivalents per kg. Logistic regression evaluated associations with clinical comorbidities. Results: Thirty percent of neonates were exposed to both drug classes, 24% to opioids alone, and 1.5% to benzodiazepines alone. Exposure was inversely related to gestational age and varied widely across facilities. High opioid exposure (≥10 MME/kg) was associated with mechanical ventilation (aOR 3.7), vasopressors (aOR 4.6), oxygen at 36 weeks (aOR 1.7), and severe IVH (aOR 2.5). Conclusions: Opioid and benzodiazepine use is common and variable in extremely preterm neonates. Standardized pain management and long-term outcome studies are urgently needed.