Neurodevelopmental and mental health outcomes in preterm infants: effects of exposures to opioid analgesic, anesthetic and sedative agents
Embargo Date
2028-02-11
OA Version
Citation
Abstract
BACKGROUND: Preterm infants are routinely exposed to various classes of analgesic, sedative, and anesthetic agents. Several pre-clinical studies on rodents and nonhuman primates have demonstrated that exposure to sedative and anesthetic agents is associated with neurotoxicity in the developing brain. In 2016, the United States Food and Drug Administration announced, in a black box warning, that “repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains,” suggesting that these medications should be administered with caution. However, further research must be conducted to thoroughly comprehend how, or if, anesthetic exposure during early life affects human brain development. Infants (particularly pre-term infants), children with chronic medical conditions, and children with acute critical illnesses are thought to be particularly at risk for neurotoxicity. Understanding the variability in opioid analgesic, sedative, and anesthetic agents used in the neonatal intensive care unit (NICU) as site-to-site variation will provide key information on exposure risk and is a critical initial step to better understand neurodevelopmental outcomes in this vulnerable population.
OBJECTIVE: To characterize the trends in types of drugs, drug dose, duration, and co-exposure to opioid analgesic, sedative, and anesthetic agents of preterm infants from 2010 to 2023 at Boston Children’s Hospital.
METHODS: The initial phase of the study, described in this thesis, is to retrospectively analyze sedation practices at Boston Children’s Hospital in pre-term infants. The proposed retrospective cohort study design will involve comprehensive data collection with respect to analgesic and sedative drug exposures in preterm infants of various institutions from Boston Children’s Hospital (BCH), including three cohorts: NICU Preterm Cohort, Surgical Preterm Cohort, and Preterm Birth Cohort.
RESULTS: The result of this study provides key information regarding drug exposure in preterm infants. The drugs analyzed in this study are characterized by classes: opioid analgesics (MME/kg), benzodiazepines (LME/kg), intravenous anesthetics or sedatives (including propofol, ketamine, and dexmedetomidine), neuromuscular blocking agents, and other agents. We were able to assess trends in drug management of preterm infants at BCH from 2007 to 2023 between the NICU and Surgical Preterm Cohorts (n=686). The Surgical Preterm Cohort had a significantly higher frequency of drug exposures across all three drug classes (opioid analgesics, benzodiazepines, intravenous anesthetics/sedative agents), with higher average doses and increased variability within the cohort compared to the NICU Preterm Cohort (p < 0.05). Length of admission highly impacted drug exposure (p < 0.001), indicating that longer hospitalizations are associated with increased analgesic, sedative, and anesthetic agent exposures. An analysis of trends over time showed that there was a strong association between opioid drug exposure and year of admission (p < 0.05), but further evaluation of these values did not indicate a clear association over time. The use of benzodiazepines and intravenous anesthetics/sedatives did not show significant variations over time (p > 0.05).
CONCLUSIONS: The Surgical Preterm Cohort received significantly higher opioid analgesic, sedative, and anesthetic agent exposures, with length of admission being the most significant determinant of opioid and benzodiazepine exposure. Temporal trends (2007-2016) in opioid exposure may suggest some changes in clinical management over time, while benzodiazepine and intravenous anesthetic/sedative agent management remained stable over the years. This study provides important information regarding drug exposures of preterm infants, highlighting the effects of surgical interventions, length of hospitalizations, and clinical management practices on drug exposures. Future studies will build upon this data to better characterize the comparability of clinical sites and NICU levels, as well as the demographic and clinical characteristics of patients receiving care at these institutions.
Description
2025