PMID- 34232302 OWN - NLM STAT- MEDLINE DCOM- 20220103 LR - 20220103 IS - 2574-3805 (Electronic) IS - 2574-3805 (Linking) VI - 4 IP - 7 DP - 2021 Jul 1 TI - Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines. PG - e2115998 LID - 10.1001/jamanetworkopen.2021.15998 [doi] LID - e2115998 AB - IMPORTANCE: Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood. OBJECTIVES: To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs' association with neurodevelopmental outcomes at 2 years' corrected age. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020. EXPOSURES: Short (ie, 7 days) exposure to opioids and/or benzodiazepines during NICU stay. MAIN OUTCOMES AND MEASURES: Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III). RESULTS: There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: -5.72; 95% CI, -8.88 to -2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure. CONCLUSIONS AND RELEVANCE: In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years' corrected age. FAU - Puia-Dumitrescu, Mihai AU - Puia-Dumitrescu M AD - Division of Neonatology, Department of Pediatrics, University of Washington, Seattle. FAU - Comstock, Bryan A AU - Comstock BA AD - Department of Biostatistics, University of Washington, Seattle. FAU - Li, Sijia AU - Li S AD - Department of Biostatistics, University of Washington, Seattle. FAU - Heagerty, Patrick J AU - Heagerty PJ AD - Department of Biostatistics, University of Washington, Seattle. FAU - Perez, Krystle M AU - Perez KM AD - Division of Neonatology, Department of Pediatrics, University of Washington, Seattle. FAU - Law, Janessa B AU - Law JB AD - Division of Neonatology, Department of Pediatrics, University of Washington, Seattle. FAU - Wood, Thomas R AU - Wood TR AD - Division of Neonatology, Department of Pediatrics, University of Washington, Seattle. FAU - Gogcu, Semsa AU - Gogcu S AD - Division of Neonatology, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina. FAU - Mayock, Dennis E AU - Mayock DE AD - Division of Neonatology, Department of Pediatrics, University of Washington, Seattle. FAU - Juul, Sandra E AU - Juul SE AD - Division of Neonatology, Department of Pediatrics, University of Washington, Seattle. CN - PENUT Consortium LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20210701 PL - United States TA - JAMA Netw Open JT - JAMA network open JID - 101729235 RN - 0 (Analgesics, Opioid) RN - 12794-10-4 (Benzodiazepines) SB - IM MH - Analgesics, Opioid/*standards/therapeutic use MH - Benzodiazepines/*standards/therapeutic use MH - Cohort Studies MH - Female MH - Humans MH - Infant MH - Infant, Extremely Premature/*metabolism/physiology MH - Infant, Newborn MH - Male MH - Neurodevelopmental Disorders/*drug therapy/physiopathology MH - Outcome Assessment, Health Care/methods/*statistics & numerical data PMC - PMC8264640 COIS- Conflict of Interest Disclosures: None reported. FIR - Wadhawan, Rajan IR - Wadhawan R FIR - Courtney, Sherry E IR - Courtney SE FIR - Robinson, Tonya IR - Robinson T FIR - Ahmad, Kaashif A IR - Ahmad KA FIR - Bendel-Stenzel, Ellen IR - Bendel-Stenzel E FIR - Baserga, Mariana IR - Baserga M FIR - LaGamma, Edmund F IR - LaGamma EF FIR - Downey, L Corbin IR - Downey LC FIR - Rao, Raghavendra IR - Rao R FIR - Fahim, Nancy IR - Fahim N FIR - Lampland, Andrea IR - Lampland A FIR - Frantz, Ivan D 3rd IR - Frantz ID 3rd FIR - Khan, Janine IR - Khan J FIR - Weiss, Michael IR - Weiss M FIR - Gilmore, Maureen M IR - Gilmore MM FIR - Ohls, Robin K IR - Ohls RK FIR - Lowe, Jean IR - Lowe J FIR - Srinivasan, Nishant IR - Srinivasan N FIR - Perez, Jorge E IR - Perez JE FIR - McKay, Victor IR - McKay V EDAT- 2021/07/08 06:00 MHDA- 2022/01/04 06:00 PMCR- 2021/07/07 CRDT- 2021/07/07 12:20 PHST- 2021/07/07 12:20 [entrez] PHST- 2021/07/08 06:00 [pubmed] PHST- 2022/01/04 06:00 [medline] PHST- 2021/07/07 00:00 [pmc-release] AID - 2781683 [pii] AID - zoi210479 [pii] AID - 10.1001/jamanetworkopen.2021.15998 [doi] PST - epublish SO - JAMA Netw Open. 2021 Jul 1;4(7):e2115998. doi: 10.1001/jamanetworkopen.2021.15998.