Cumulative Exposure to Opioids and Benzodiazepines in Extremely Preterm Neonates

Cumulative Exposure to Opioids and Benzodiazepines in Extremely Preterm Neonates | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Cumulative Exposure to Opioids and Benzodiazepines in Extremely Preterm Neonates Michael Kuzniewicz, Lena Sun, Aditi Lahiri, Shawn Jackson, Jonathan Davis This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7105002/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Nov, 2025 Read the published version in Journal of Perinatology → Version 1 posted 7 You are reading this latest preprint version 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. Health sciences/Medical research/Outcomes research Health sciences/Medical research/Epidemiology Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Preterm neonates often undergo painful procedures or require mechanical ventilation, with the most premature infants experiencing the highest number of painful events and longest duration of ventilation. 1 , 2 Exposure to both acute and chronic pain has been linked to reduced brain growth in the frontal and parietal lobes as well as changes in brain organization and neuronal connections. 3 , 4 This can result in increased stress sensitivity, hyperalgesia, behavioral changes, and impaired neurodevelopment. 3 – 8 This has led to a strong emphasis on assessing pain and stress in neonates along with implementing both non-pharmacologic and pharmacologic treatment strategies. 2 , 9 The most common drugs used for pain and sedation in the neonatal intensive care unit (NICU) are opioids and benzodiazepines, both of which are linked with adverse outcomes. Opioid exposure has been associated with impaired cortical and cerebellar growth. 10 , 11 The long-term impact on motor and cognitive outcomes remains uncertain, with some studies reporting worse neurodevelopmental outcomes associated with opioid exposure 10 , 12 – 14 , while others show no clear differences between exposed and unexposed neonates. 15 – 17 Benzodiazepines have been shown to induce neuronal apoptosis and increase the risk of brain injury in developing rodents. 18 , 19 Benzodiazepine administration to preterm neonates has been associated with adverse neurologic outcomes. 20 , 21 Alternative medications such as methadone, ketamine, propofol, and dexmedetomidine are increasingly being used for pain management in preterm neonates. However, data on the safety of these agents in this population is lacking. 22 , 23 Assessing pain in extremely preterm, critically ill, or neurologically compromised neonates is extremely subjective and can be especially challenging. Furthermore, the lack of clear guidelines for neonatal pain management and effective strategies for pain and sedation during intubation and mechanical ventilation likely leads to marked variability in practice. Quantifying the variability in exposure may help elucidate the relationship between the use of these drugs and long-term neurodevelopmental outcomes as well as offer opportunities for improved stewardship of these medications. Additionally, examining neonates with the greatest exposure (since these may also be the sickest and most complex patients) may provide further insights on risk factors associated with neurodevelopmental impairment in this particularly vulnerable population. Our objective was to quantify exposure of opioids and benzodiazepines in preterm neonates and identify how these exposures differ by gestational age, facility, and comorbid conditions/treatments. METHODS Study Design and Population We conducted a cross-sectional study involving neonates born at 23 0/7 to 28 6/7 weeks gestation at Kaiser Permanente Northern California (KPNC) facilities from January 1, 2011, to December 31, 2021. The study excluded deaths within the first 7 days after birth. KPNC includes 15 delivery hospitals and 7 Level III Community Neonatal Intensive Care Units (NICUs). Three of the facilities operate as regional referral centers within KP for pediatric surgery, pediatric neurosurgery, and pediatric neurologic services. Four of the facilities perform pediatric surgery. Facilities have between 20–24 licenses NICU beds, except for one facility with 60 licensed beds. Details of each individual facility and patient characteristics are presented in Supplemental Tables 1 and 2. While the sociodemographic distribution of KPNC membership closely resembles that of the local and state-wide California population, it does not fully represent the extremes of income distribution. 24 The KPNC Institutional Review Board approved the research. Exposure Data Data were obtained from the electronic medication administration record (eMAR) on opioid, benzodiazepine, dexmedetomidine, propofol, ketamine, and neuromuscular blockade use. For opioids and benzodiazepines, we characterized the exposure variable as the cumulative number of days each neonate was exposed to opioids and/or benzodiazepines. The exposure was captured as yes or no on any given day, without accounting for concurrent administration of more than one medication of interest. Short exposure was defined as a neonate who received the medications of interest less than 7 days. Prolonged exposure occurred if the neonate received a cumulative exposure to the medications of interest for 7 days or more. Morphine milligram equivalents (MME) per kilogram were calculated for all opioid administrations (discrete doses and infusions). For calculations, the dosing weight in the eMAR for the specific drug order was used. If unavailable, the daily weight was obtained in the electronic health record (EHR). Standard conversion factors were used: oral morphine 0.1mg/kg/dose = 0.1 MME/kg/dose; intravenous morphine 0.1mg/kg/dose = 0.3 MME/kg/dose; intravenous fentanyl 1mcg/kg/dose = 0.3 MME/kg/dose; methadone 0.1mg/kg/dose = 0.4 MME/kg/dose. Similarly, lorazepam milligram equivalents (LME) per kilogram were calculated for all benzodiazepine administration (both discrete doses and infusions). Cumulative dosage of opioids and benzodiazepines over the entire hospitalization were calculated. Covariates Demographic information (payor source, maternal and neonatal race/ethnicity, and standardized neighborhood deprivation index) was extracted from EHR. Mechanical ventilation and receipt of supplemental oxygen at 36 weeks post-menstrual age were derived from the inpatient respiratory flowsheets. Data on inotropes and vasopressors was obtained from the electronic medical administration record. Severe intraventricular hemorrhage (IVH) was defined as Grade 3 or Grade 4 hemorrhage noted on head ultrasound. Severe retinopathy of prematurity (ROP) included any infant with Stage 3 or worse ROP or if the neonate received treatment with laser therapy or bevacizumab. A diagnosis of necrotizing enterocolitis (NEC) was determined: 1) at the time of surgery, 2) at postmortem examination, or 3) in neonates with radiologic evidence (pneumatosis intestinalis, hepato-biliary gas, pneumoperitoneum) and one or more clinical findings (bilious gastric aspirate or emesis, abdominal distention, occult or gross blood in stool). Statistical methods Descriptive statistics and graphic illustrations were used to describe the demographic and baseline maternal and neonatal characteristics. Logistic regression was used to evaluate the association between comorbidities/treatments and ≥ 10 MME/kg opioid exposure or ≥ 2 lorazepam equivalent mg/kg, adjusting for antenatal steroids, sex, and gestational age RESULTS The study included 1,501 infants born between 23–28 weeks’ gestation that survived to at least 7 days after birth. Characteristics of the study population and incidence of mortality and inpatient morbidities for the overall population and by facility are presented in Table 1 . In the overall population, exposure to antenatal corticosteroids prior to delivery was 94%, mean birthweight 939 grams (SD 240 grams), and 13% (n = 196) were less than 25 weeks’ gestation at birth. Table 1 Characteristics and Outcomes of Patient Population Characteristic/outcome (n = 1,501 Infants) Male, n (%) 811 (54%) Birthweight (grams); mean (SD) 939 (240) GA 23–24 weeks, n (%) 196 (13%) GA 25–28 weeks, n (%) 1,305 (87%) Antenatal Steroids, n (%) 1,413 (94%) Mechanical ventilation, n (%) 853 (57%) Death, n (%) 103 (7%) Severe ROP, n (%) 140 (9%) Severe IVH, n (%) 86 (6%) Bacterial infection, n (%) 158 (11%) GA – gestational age; ROP – retinopathy of prematurity; IVH – intraventricular hemorrhage Overall exposure to any opioids or any benzodiazepines was 53% (n = 801) and 31% (n = 467), respectively. Exposure to opioids and benzodiazepines was inversely associated with gestational age (GA). Neonates of lower gestational age at birth were also more likely to receive 7 or more days of treatment of either medication class (Fig. 1 A and 1 B). Among neonates born at 23- or 24-weeks’ gestation, 91% were exposed to opioids and 74% received more than seven days of therapy. These neonates received significantly more opioids compared to neonates born at 28 weeks’ gestation, OR 2.9 (95%CI 2.4–3.4). Similarly, neonates born at 23- or 24-weeks’ gestation were more likely to receive benzodiazepines compared to those born at 28 weeks’ gestation, OR 2.4 (95%CI 2.0 -2.8). The distribution of cumulative exposure to opioids and benzodiazepines during the entire hospital course was highly right skewed (Figs. 2 A and 2 B) with 67% of those exposed to opioids receiving a cumulative dose of < 10 MME/kg and 69% of those exposed to benzodiazepines receiving a cumulative dose of < 2 LME/kg. However, 9.4% of those exposed to opioids received a cumulative dose of ≥ 50 MME/kg and 15% of those exposed to benzodiazepines received a cumulative dose of ≥ 5 LME/kg. Examining cumulative exposure by gestational age (Figs. 2 C and 2 D), the highest opioid exposure was in neonates born at 23-weeks’ gestation with a median exposure of 6.6 MME/kg (IQR1.6–28.7), at 24-weeks’ gestation 7.3 MME/kg (IQR1.3–27.2), and at 25-weeks’ gestation 2.2 MME/kg (IQR 0.2– 21). By 26 weeks’ gestation, less than 50% of neonates were exposed to any opioids. However, there were outliers with substantial cumulative opioid exposure > 10 MME/kg at all gestational ages. Cumulative benzodiazepine exposure followed a similar pattern stratified by gestational age. There was substantial co-exposure between opioids and benzodiazepines (Table 2 ). Benzodiazepine exposure increased as the cumulative opioid exposure increased with 93% of those exposed to ≥ 30 MME/kg receiving some benzodiazepines. While overall exposure to dexmedetomidine, propofol, and ketamine were low (< 5%), the use of these medications increased with cumulative MME/kg exposure. Neuromuscular blockade agents were used in 15% of the population but increased to ≥ 30% if cumulative opioid exposure was ≥ 2 MME/kg. Table 2 Co-exposures with Opioids Medication Any Opioids Cumulative MME (mg/kg) None < 2 2-9.9 10–29 ≥ 30 Benzodiazepines 31% 4% 29% 66% 76% 93% Dexmedetomidine 2% 0.3% 1% 2% 5% 13% Propofol 3% 0% 2% 5% 9% 12% Ketamine 0.3% 0% 0% 0.6% 0% 2% Neuromuscular blockade 15% 0.3% 14% 34% 32% 60% Significant variation existed among facilities regarding any exposure to opioids and/or benzodiazepines as well as cumulative exposure (Fig. 3 ). We observed the lowest opioid exposure in facility D (25%), a regional center with pediatric surgery compared to facilities B and G with 79% and 80% exposure. In facility D, only 4% of neonates received a cumulative exposure of ≥ 10 MME/kg. In facilities B, F, and G, the percentage with cumulative exposure of ≥ 10 MME/kg was 28%, 34%, and 28%, respectively (Fig. 3 A). Benzodiazepine exposure showed similar variation, with the lowest exposure in facility D (16%) and highest in facility B (52%) (Fig. 3 B). Cumulative exposure of ≥ 2 LME/kg was present in greater 10% of neonates in facilities B, F, and G and less than 4% of those in Facilities D and E. Examining interfacility variation of opioids and benzodiazepine exposure by gestational age strata (Figs. 3 C and 3 D), substantial variation persisted among centers within each stratum. Although most neonates < 25 weeks gestation (regardless of facility) received opioids, the cumulative exposure in the gestational age strata differed by facility. Similar patterns were seen in terms of cumulative benzodiazepine exposure. Cumulative opioid exposure ≥ 10MME/kg was associated with the need for mechanical ventilation adjusted odds ratio (aOR) 3.7 (95%Confidence Interval [CI] 2.5–5.4), inotropes/vasopressors aOR 4.6 (95%CI 3.4–6.4), supplemental O 2 at 36 weeks post-menstrual age aOR 1.7 (95%CI 1.3–2.4), and severe intraventricular hemorrhage: aOR 2.5 (95%CI 1.5–4.1). DISCUSSION In this large, multicenter cohort of 1,501 extremely preterm neonates (23–28 weeks gestation), we found that over half were exposed to opioids and nearly one-third to benzodiazepines during their NICU stay. Exposure was inversely associated with gestational age and varied substantially across facilities, both in incidence and cumulative dose. Notably, higher cumulative opioid exposure (≥ 10 MME/kg) was strongly associated with clinical indicators of illness severity, including mechanical ventilation, vasopressor use, oxygen requirement at 36 weeks postmenstrual age, and severe intraventricular hemorrhage. These findings underscore the complexity of pharmacologic pain management in the NICU and raise concerns about variability in practice and potential for long-term neurodevelopmental impairment. These findings reinforce prior studies documenting widespread use of sedative-analgesic medications in preterm populations and highlight the persistent variability in practice across NICUs. 13 , 25 – 27 A study of 20,744 preterm neonates in Canadian NICUs between 2010 and 2014 found that 29% received a narcotic, a sedative, or both; 23% received a narcotic, and 17% a sedative. 27 Significant variations in narcotic and sedative use existed between sites, ranging from 3% − 41% for narcotics and 2% − 48% for sedatives. Similar variation has been observed across European NICUs. 26 Variability in sedative-analgesic medications use by site also exists within the United States. In the Preterm Erythropoietin Neuroprotection (PENUT) Trial, data from 19 hospitals showed that mean opioid use was 81% (range 50%-100%) and mean benzodiazepines use was 52% (range 7%-93%). 13 . Our study adds to this literature by providing a granular, cross-institutional view within a single integrated healthcare system, revealing that even among facilities with shared infrastructure, exposure rates and dosing practices differ markedly. The clinical implications of this variability are significant. While pharmacologic pain management is essential in the NICU, especially for neonates requiring mechanical ventilation or undergoing invasive procedures, the potential neurotoxic effects of opioids and benzodiazepines on the developing brain are increasingly recognized. 28 , 29 In the NEOPAIN trial, a landmark study evaluating morphine use in ventilated preterm neonates, opioid administration was associated with increased incidence of hypotension and prolonged ventilation, although the study was not powered to assess long-term neurodevelopmental outcomes. 20 More recent work by Puia-Dumitrescu et al. assessed neurodevelopmental outcomes at two years among extremely preterm neonates and found that cumulative opioid and/or benzodiazepine exposure was associated with significantly lower Bayley Scales of Infant Development (BSID-III) scores in motor and cognitive domains. 13 Notably, their study also identified a dose-response relationship, where higher cumulative exposure yielded poorer outcomes—an observation aligned with our findings that ≥ 10 MME/kg opioid exposure was strongly associated with comorbidities that themselves are associated with adverse neurodevelopmental outcome. Similarly, a recent large French cohort study reported five-year follow-up data and demonstrated significantly increased risk of neurodevelopmental delay in children born very preterm (24–31 weeks) who were exposed to opioids with or without midazolam. 30 These findings support our conclusion that opioid and benzodiazepine exposure in the NICU, especially at higher doses, may contribute to long-term developmental sequelae. Importantly, the French study emphasized that even short-term exposures (especially repeated dosing or at high doses) carried similar risks—raising questions about current definitions of “short” versus “prolonged” exposure. Importantly, our data suggest that institutional practices—rather than patient characteristics alone—may drive much of the observed variation. For instance, Facility D had significantly lower exposure rates and cumulative doses compared to Facilities B and G, despite caring for similarly preterm populations. This suggests opportunities for quality improvement and standardization of pain management protocols. Facilities with lower exposure may serve as models for effective, lower-risk approaches to sedation and analgesia. Our study further adds to the limited literature evaluating polypharmacy in the NICU. The high rate of co-exposure to opioids and benzodiazepines (especially among those receiving ≥ 30 MME/kg) underscores the need to consider cumulative sedative burden. This variation in practice is concerning given the potential for neurotoxic effects of both drug classes. Benzodiazepines have been implicated in hippocampal growth abnormalities and impaired neurocognitive outcomes. 31 Although use of adjunctive agents like dexmedetomidine, ketamine, and propofol was infrequent, their increased use in neonates with high opioid exposure suggests a trend toward polypharmacy in the sickest patients. Although these newer agents may offer advantages such as reduced respiratory depression or neuroprotection in animal models, data on safety and efficacy in preterm neonates is extremely limited. 22 , 23 Our findings point to an urgent need for comparative effectiveness trials that evaluate both short-term safety and efficacy and longer-term neurodevelopmental outcome. Studies need to focus on these long-term neurodevelopmental outcomes, particularly higher-order cognitive functions like memory, attention, and executive functioning. These skills develop later in childhood and are more sensitive to subtle brain injuries. 28 The association between high cumulative opioid exposure and severe intraventricular hemorrhage, mechanical ventilation, vasoactive agents, and bronchopulmonary dysplasia observed in our cohort raises questions about causality versus confounding. It is plausible that neonates with these interventions or complications experience more pain and agitation, necessitating more pharmacologic interventions. However, opioid exposure itself has been shown to lower blood pressure, disrupt cerebral autoregulation, reduce cortical perfusion, and impair cerebellar growth which could exacerbate the risk of brain injury. 10 , 11 , 32 Future studies integrating real-time neuroimaging and pain scoring may help delineate whether opioid exposure contributes to brain injury or is a marker of illness severity. Several limitations of our study must be acknowledged. First, the retrospective nature of exposure assessment may not fully capture every change in dosing or the concurrent use of non-pharmacologic pain interventions. Second, while we calculated MME and LME per kilogram, we did not analyze pharmacokinetics or cumulative plasma concentrations, which may vary significantly across neonates. Third, the lack of neurodevelopmental outcome data precludes direct assessment of long-term consequences, though our findings align with studies that do report such outcomes. Despite these limitations, our study provides a valuable real-world snapshot of opioid and benzodiazepine use in a diverse cohort of preterm neonates. It identifies key patient and facility-level drivers of exposure and highlights areas for potential stewardship and quality improvement. Institutions with lower exposure rates may serve as models for protocols that balance effective pain management with minimizing neurotoxic risk. In conclusion, our study highlights the widespread and variable use of opioids and benzodiazepines in extremely preterm neonates, particularly among those with greater illness severity. Given the growing evidence of potential neurotoxicity, there is a pressing need to standardize pain management practices, reduce unnecessary exposure, and rigorously evaluate long-term outcomes. Future research should focus on identifying optimal dosing strategies, integrating multimodal analgesia, and developing individualized, risk-informed approaches to sedation in this vulnerable population. Declarations Acknowledgments and Funding Disclosure: Funded in part by a grant from the US Food and Drug Administration U01FD007702. Conflicts of Interest The authors have no conflicts of interest to disclose. Authorship All authors contributed to the: 1. Conception and design of the work 2. The acquisition, analysis, and interpretation of data 3. Drafting the work and reviewing it critically for important intellectual content 4. Final approval of the version to be published References Carbajal R, Rousset A, Danan C, et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 2008;300:60–70. Committee on the Fetus and Newborn, Section on Pain, Prevention, and Management of Procedural Pain in the Neonate: An Update. Pediatrics 2016;137:e20154271. 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Supplementary Files Kuzniewiczopioidssupplementaltables11July2025.docx Supplemental Material Cite Share Download PDF Status: Published Journal Publication published 27 Nov, 2025 Read the published version in Journal of Perinatology → Version 1 posted Editorial decision: revise 18 Aug, 2025 Review # 1 received at journal 07 Aug, 2025 Reviewer # 1 agreed at journal 31 Jul, 2025 Reviewers invited by journal 15 Jul, 2025 Submission checks completed at journal 14 Jul, 2025 Editor assigned by journal 11 Jul, 2025 First submitted to journal 11 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7105002","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":485880552,"identity":"61e84288-c623-4094-9782-3635b64176b5","order_by":0,"name":"Michael Kuzniewicz","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-3271-2999","institution":"Kaiser Permanente Northern California, Division of Research","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"","lastName":"Kuzniewicz","suffix":""},{"id":485880553,"identity":"bbb77ae2-9051-46c6-b1d3-cc9468e33c90","order_by":1,"name":"Lena Sun","email":"","orcid":"https://orcid.org/0000-0002-1100-8492","institution":"Columbia University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Lena","middleName":"","lastName":"Sun","suffix":""},{"id":485880554,"identity":"0ebac46b-faf8-455d-9bc3-eeb204ff4fd8","order_by":2,"name":"Aditi Lahiri","email":"","orcid":"","institution":"Kaiser Permanente Northern California","correspondingAuthor":false,"prefix":"","firstName":"Aditi","middleName":"","lastName":"Lahiri","suffix":""},{"id":485880555,"identity":"bf776030-abfd-4d05-9163-2fa72e45a4b7","order_by":3,"name":"Shawn Jackson","email":"","orcid":"","institution":"Boston Children's Hospital/Harvard MEdical School","correspondingAuthor":false,"prefix":"","firstName":"Shawn","middleName":"","lastName":"Jackson","suffix":""},{"id":485880556,"identity":"0f9ec299-05fb-49e5-bbf5-6c1e88dbe6b9","order_by":4,"name":"Jonathan Davis","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"","lastName":"Davis","suffix":""}],"badges":[],"createdAt":"2025-07-12 01:10:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7105002/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7105002/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41372-025-02513-9","type":"published","date":"2025-11-27T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87050768,"identity":"8c9c8dee-e331-458a-8cee-e58da25dbdd2","added_by":"auto","created_at":"2025-07-18 14:59:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":242574,"visible":true,"origin":"","legend":"\u003cp\u003eDuration (Cumulative Days) of Opioid Use (1A) and Benzodiazepine Use (1B) by Gestational Age\u003c/p\u003e","description":"","filename":"Figure1DurationbyGA.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7105002/v1/bed3af010215ca3c83e316e9.jpg"},{"id":87050777,"identity":"20cee637-66aa-448b-8140-d2e30ab23e35","added_by":"auto","created_at":"2025-07-18 14:59:20","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":436686,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative Exposure to Opioids (Absolute - 2A) and by Gestational Age (2C) and Benzodiazepines (Absolute – 2B) and by Gestational Age (2D)\u003c/p\u003e","description":"","filename":"Figure2CumulativeExposure.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7105002/v1/870e0368c7dff8b8db0d5fa8.jpg"},{"id":87050775,"identity":"0b3f8041-248e-4d19-ba49-301955f81f2f","added_by":"auto","created_at":"2025-07-18 14:59:20","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":344213,"visible":true,"origin":"","legend":"\u003cp\u003eExposure to Opioids and Benzodiazepines by Facility\u003c/p\u003e","description":"","filename":"Figure3ByFacility.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7105002/v1/29f005dcce00039303fe0493.jpg"},{"id":96975447,"identity":"d1af1056-29eb-4b3e-bae2-513420ac94ab","added_by":"auto","created_at":"2025-11-28 08:25:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1505483,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7105002/v1/cd6d8000-59f1-4af6-b694-8929f66eab68.pdf"},{"id":87052184,"identity":"cd9d6f11-6fdc-4c75-b2ee-4733282162a4","added_by":"auto","created_at":"2025-07-18 15:07:19","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21400,"visible":true,"origin":"","legend":"Supplemental Material","description":"","filename":"Kuzniewiczopioidssupplementaltables11July2025.docx","url":"https://assets-eu.researchsquare.com/files/rs-7105002/v1/2380830535f08a9e211fecf7.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"\u003cp\u003eCumulative Exposure to Opioids and Benzodiazepines in Extremely Preterm Neonates\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePreterm neonates often undergo painful procedures or require mechanical ventilation, with the most premature infants experiencing the highest number of painful events and longest duration of ventilation.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Exposure to both acute and chronic pain has been linked to reduced brain growth in the frontal and parietal lobes as well as changes in brain organization and neuronal connections.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e This can result in increased stress sensitivity, hyperalgesia, behavioral changes, and impaired neurodevelopment.\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6 CR7\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e This has led to a strong emphasis on assessing pain and stress in neonates along with implementing both non-pharmacologic and pharmacologic treatment strategies.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe most common drugs used for pain and sedation in the neonatal intensive care unit (NICU) are opioids and benzodiazepines, both of which are linked with adverse outcomes. Opioid exposure has been associated with impaired cortical and cerebellar growth.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e The long-term impact on motor and cognitive outcomes remains uncertain, with some studies reporting worse neurodevelopmental outcomes associated with opioid exposure\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e–\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, while others show no clear differences between exposed and unexposed neonates.\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e–\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Benzodiazepines have been shown to induce neuronal apoptosis and increase the risk of brain injury in developing rodents.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Benzodiazepine administration to preterm neonates has been associated with adverse neurologic outcomes.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Alternative medications such as methadone, ketamine, propofol, and dexmedetomidine are increasingly being used for pain management in preterm neonates. However, data on the safety of these agents in this population is lacking.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eAssessing pain in extremely preterm, critically ill, or neurologically compromised neonates is extremely subjective and can be especially challenging. Furthermore, the lack of clear guidelines for neonatal pain management and effective strategies for pain and sedation during intubation and mechanical ventilation likely leads to marked variability in practice. Quantifying the variability in exposure may help elucidate the relationship between the use of these drugs and long-term neurodevelopmental outcomes as well as offer opportunities for improved stewardship of these medications. Additionally, examining neonates with the greatest exposure (since these may also be the sickest and most complex patients) may provide further insights on risk factors associated with neurodevelopmental impairment in this particularly vulnerable population.\u003c/p\u003e\u003cp\u003eOur objective was to quantify exposure of opioids and benzodiazepines in preterm neonates and identify how these exposures differ by gestational age, facility, and comorbid conditions/treatments.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cb\u003eStudy Design and Population\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe conducted a cross-sectional study involving neonates born at 23\u003csup\u003e0/7\u003c/sup\u003e to 28\u003csup\u003e6/7\u003c/sup\u003e weeks gestation at Kaiser Permanente Northern California (KPNC) facilities from January 1, 2011, to December 31, 2021. The study excluded deaths within the first 7 days after birth. KPNC includes 15 delivery hospitals and 7 Level III Community Neonatal Intensive Care Units (NICUs). Three of the facilities operate as regional referral centers within KP for pediatric surgery, pediatric neurosurgery, and pediatric neurologic services. Four of the facilities perform pediatric surgery. Facilities have between 20–24 licenses NICU beds, except for one facility with 60 licensed beds. Details of each individual facility and patient characteristics are presented in Supplemental Tables\u0026nbsp;1 and 2. While the sociodemographic distribution of KPNC membership closely resembles that of the local and state-wide California population, it does not fully represent the extremes of income distribution.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e The KPNC Institutional Review Board approved the research.\u003c/p\u003e\u003cp\u003e\u003cb\u003eExposure Data\u003c/b\u003e\u003c/p\u003e\u003cp\u003eData were obtained from the electronic medication administration record (eMAR) on opioid, benzodiazepine, dexmedetomidine, propofol, ketamine, and neuromuscular blockade use. For opioids and benzodiazepines, we characterized the exposure variable as the cumulative number of days each neonate was exposed to opioids and/or benzodiazepines. The exposure was captured as yes or no on any given day, without accounting for concurrent administration of more than one medication of interest. Short exposure was defined as a neonate who received the medications of interest less than 7 days. Prolonged exposure occurred if the neonate received a cumulative exposure to the medications of interest for 7 days or more. Morphine milligram equivalents (MME) per kilogram were calculated for all opioid administrations (discrete doses and infusions). For calculations, the dosing weight in the eMAR for the specific drug order was used. If unavailable, the daily weight was obtained in the electronic health record (EHR). Standard conversion factors were used: oral morphine 0.1mg/kg/dose = 0.1 MME/kg/dose; intravenous morphine 0.1mg/kg/dose = 0.3 MME/kg/dose; intravenous fentanyl 1mcg/kg/dose = 0.3 MME/kg/dose; methadone 0.1mg/kg/dose = 0.4 MME/kg/dose. Similarly, lorazepam milligram equivalents (LME) per kilogram were calculated for all benzodiazepine administration (both discrete doses and infusions). Cumulative dosage of opioids and benzodiazepines over the entire hospitalization were calculated.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCovariates\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDemographic information (payor source, maternal and neonatal race/ethnicity, and standardized neighborhood deprivation index) was extracted from EHR. Mechanical ventilation and receipt of supplemental oxygen at 36 weeks post-menstrual age were derived from the inpatient respiratory flowsheets. Data on inotropes and vasopressors was obtained from the electronic medical administration record. Severe intraventricular hemorrhage (IVH) was defined as Grade 3 or Grade 4 hemorrhage noted on head ultrasound. Severe retinopathy of prematurity (ROP) included any infant with Stage 3 or worse ROP or if the neonate received treatment with laser therapy or bevacizumab. A diagnosis of necrotizing enterocolitis (NEC) was determined: 1) at the time of surgery, 2) at postmortem examination, or 3) in neonates with radiologic evidence (pneumatosis intestinalis, hepato-biliary gas, pneumoperitoneum) and one or more clinical findings (bilious gastric aspirate or emesis, abdominal distention, occult or gross blood in stool).\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical methods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDescriptive statistics and graphic illustrations were used to describe the demographic and baseline maternal and neonatal characteristics. Logistic regression was used to evaluate the association between comorbidities/treatments and ≥ 10 MME/kg opioid exposure or ≥ 2 lorazepam equivalent mg/kg, adjusting for antenatal steroids, sex, and gestational age\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe study included 1,501 infants born between 23\u0026ndash;28 weeks\u0026rsquo; gestation that survived to at least 7 days after birth. Characteristics of the study population and incidence of mortality and inpatient morbidities for the overall population and by facility are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In the overall population, exposure to antenatal corticosteroids prior to delivery was 94%, mean birthweight 939 grams (SD 240 grams), and 13% (n\u0026thinsp;=\u0026thinsp;196) were less than 25 weeks\u0026rsquo; gestation at birth.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics and Outcomes of Patient Population\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristic/outcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;1,501 Infants)\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e811 (54%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBirthweight (grams); mean (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e939 (240)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGA 23\u0026ndash;24 weeks, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e196 (13%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGA 25\u0026ndash;28 weeks, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,305 (87%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntenatal Steroids, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,413 (94%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e853 (57%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeath, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e103 (7%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere ROP, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e140 (9%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere IVH, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e86 (6%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBacterial infection, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e158 (11%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eGA \u0026ndash; gestational age; ROP \u0026ndash; retinopathy of prematurity; IVH \u0026ndash; intraventricular hemorrhage\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOverall exposure to any opioids or any benzodiazepines was 53% (n\u0026thinsp;=\u0026thinsp;801) and 31% (n\u0026thinsp;=\u0026thinsp;467), respectively. Exposure to opioids and benzodiazepines was inversely associated with gestational age (GA). Neonates of lower gestational age at birth were also more likely to receive 7 or more days of treatment of either medication class (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Among neonates born at 23- or 24-weeks\u0026rsquo; gestation, 91% were exposed to opioids and 74% received more than seven days of therapy. These neonates received significantly more opioids compared to neonates born at 28 weeks\u0026rsquo; gestation, OR 2.9 (95%CI 2.4\u0026ndash;3.4). Similarly, neonates born at 23- or 24-weeks\u0026rsquo; gestation were more likely to receive benzodiazepines compared to those born at 28 weeks\u0026rsquo; gestation, OR 2.4 (95%CI 2.0 -2.8).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe distribution of cumulative exposure to opioids and benzodiazepines during the entire hospital course was highly right skewed (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB) with 67% of those exposed to opioids receiving a cumulative dose of \u0026lt;\u0026thinsp;10 MME/kg and 69% of those exposed to benzodiazepines receiving a cumulative dose of \u0026lt;\u0026thinsp;2 LME/kg. However, 9.4% of those exposed to opioids received a cumulative dose of \u0026ge;\u0026thinsp;50 MME/kg and 15% of those exposed to benzodiazepines received a cumulative dose of \u0026ge;\u0026thinsp;5 LME/kg. Examining cumulative exposure by gestational age (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD), the highest opioid exposure was in neonates born at 23-weeks\u0026rsquo; gestation with a median exposure of 6.6 MME/kg (IQR1.6\u0026ndash;28.7), at 24-weeks\u0026rsquo; gestation 7.3 MME/kg (IQR1.3\u0026ndash;27.2), and at 25-weeks\u0026rsquo; gestation 2.2 MME/kg (IQR 0.2\u0026ndash; 21). By 26 weeks\u0026rsquo; gestation, less than 50% of neonates were exposed to any opioids. However, there were outliers with substantial cumulative opioid exposure\u0026thinsp;\u0026gt;\u0026thinsp;10 MME/kg at all gestational ages. Cumulative benzodiazepine exposure followed a similar pattern stratified by gestational age.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThere was substantial co-exposure between opioids and benzodiazepines (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Benzodiazepine exposure increased as the cumulative opioid exposure increased with 93% of those exposed to \u0026ge;\u0026thinsp;30 MME/kg receiving some benzodiazepines. While overall exposure to dexmedetomidine, propofol, and ketamine were low (\u0026lt;\u0026thinsp;5%), the use of these medications increased with cumulative MME/kg exposure. Neuromuscular blockade agents were used in 15% of the population but increased to \u0026ge;\u0026thinsp;30% if cumulative opioid exposure was \u0026ge;\u0026thinsp;2 MME/kg.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCo-exposures with Opioids\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMedication\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAny Opioids\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c7\" namest=\"c3\"\u003e\u003cp\u003eCumulative MME (mg/kg)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2-9.9\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10\u0026ndash;29\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;30\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBenzodiazepines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e66%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e76%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e93%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDexmedetomidine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e13%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePropofol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKetamine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.6%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeuromuscular blockade\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.3%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e34%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e32%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e60%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSignificant variation existed among facilities regarding any exposure to opioids and/or benzodiazepines as well as cumulative exposure (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). We observed the lowest opioid exposure in facility D (25%), a regional center with pediatric surgery compared to facilities B and G with 79% and 80% exposure. In facility D, only 4% of neonates received a cumulative exposure of \u0026ge;\u0026thinsp;10 MME/kg. In facilities B, F, and G, the percentage with cumulative exposure of \u0026ge;\u0026thinsp;10 MME/kg was 28%, 34%, and 28%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Benzodiazepine exposure showed similar variation, with the lowest exposure in facility D (16%) and highest in facility B (52%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Cumulative exposure of \u0026ge;\u0026thinsp;2 LME/kg was present in greater 10% of neonates in facilities B, F, and G and less than 4% of those in Facilities D and E.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eExamining interfacility variation of opioids and benzodiazepine exposure by gestational age strata (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD), substantial variation persisted among centers within each stratum. Although most neonates\u0026thinsp;\u0026lt;\u0026thinsp;25 weeks gestation (regardless of facility) received opioids, the cumulative exposure in the gestational age strata differed by facility. Similar patterns were seen in terms of cumulative benzodiazepine exposure.\u003c/p\u003e\u003cp\u003eCumulative opioid exposure\u0026thinsp;\u0026ge;\u0026thinsp;10MME/kg was associated with the need for mechanical ventilation adjusted odds ratio (aOR) 3.7 (95%Confidence Interval [CI] 2.5\u0026ndash;5.4), inotropes/vasopressors aOR 4.6 (95%CI 3.4\u0026ndash;6.4), supplemental O\u003csub\u003e2\u003c/sub\u003e at 36 weeks post-menstrual age aOR 1.7 (95%CI 1.3\u0026ndash;2.4), and severe intraventricular hemorrhage: aOR 2.5 (95%CI 1.5\u0026ndash;4.1).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this large, multicenter cohort of 1,501 extremely preterm neonates (23\u0026ndash;28 weeks gestation), we found that over half were exposed to opioids and nearly one-third to benzodiazepines during their NICU stay. Exposure was inversely associated with gestational age and varied substantially across facilities, both in incidence and cumulative dose. Notably, higher cumulative opioid exposure (\u0026ge;\u0026thinsp;10 MME/kg) was strongly associated with clinical indicators of illness severity, including mechanical ventilation, vasopressor use, oxygen requirement at 36 weeks postmenstrual age, and severe intraventricular hemorrhage. These findings underscore the complexity of pharmacologic pain management in the NICU and raise concerns about variability in practice and potential for long-term neurodevelopmental impairment.\u003c/p\u003e\u003cp\u003eThese findings reinforce prior studies documenting widespread use of sedative-analgesic medications in preterm populations and highlight the persistent variability in practice across NICUs.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e A study of 20,744 preterm neonates in Canadian NICUs between 2010 and 2014 found that 29% received a narcotic, a sedative, or both; 23% received a narcotic, and 17% a sedative.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Significant variations in narcotic and sedative use existed between sites, ranging from 3% \u0026minus;\u0026thinsp;41% for narcotics and 2% \u0026minus;\u0026thinsp;48% for sedatives. Similar variation has been observed across European NICUs.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Variability in sedative-analgesic medications use by site also exists within the United States. In the Preterm Erythropoietin Neuroprotection (PENUT) Trial, data from 19 hospitals showed that mean opioid use was 81% (range 50%-100%) and mean benzodiazepines use was 52% (range 7%-93%).\u003csup\u003e13\u003c/sup\u003e. Our study adds to this literature by providing a granular, cross-institutional view within a single integrated healthcare system, revealing that even among facilities with shared infrastructure, exposure rates and dosing practices differ markedly.\u003c/p\u003e\u003cp\u003eThe clinical implications of this variability are significant. While pharmacologic pain management is essential in the NICU, especially for neonates requiring mechanical ventilation or undergoing invasive procedures, the potential neurotoxic effects of opioids and benzodiazepines on the developing brain are increasingly recognized.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e In the NEOPAIN trial, a landmark study evaluating morphine use in ventilated preterm neonates, opioid administration was associated with increased incidence of hypotension and prolonged ventilation, although the study was not powered to assess long-term neurodevelopmental outcomes.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e More recent work by Puia-Dumitrescu et al. assessed neurodevelopmental outcomes at two years among extremely preterm neonates and found that cumulative opioid and/or benzodiazepine exposure was associated with significantly lower Bayley Scales of Infant Development (BSID-III) scores in motor and cognitive domains.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Notably, their study also identified a dose-response relationship, where higher cumulative exposure yielded poorer outcomes\u0026mdash;an observation aligned with our findings that \u0026ge;\u0026thinsp;10 MME/kg opioid exposure was strongly associated with comorbidities that themselves are associated with adverse neurodevelopmental outcome. Similarly, a recent large French cohort study reported five-year follow-up data and demonstrated significantly increased risk of neurodevelopmental delay in children born very preterm (24\u0026ndash;31 weeks) who were exposed to opioids with or without midazolam.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e These findings support our conclusion that opioid and benzodiazepine exposure in the NICU, especially at higher doses, may contribute to long-term developmental sequelae. Importantly, the French study emphasized that even short-term exposures (especially repeated dosing or at high doses) carried similar risks\u0026mdash;raising questions about current definitions of \u0026ldquo;short\u0026rdquo; versus \u0026ldquo;prolonged\u0026rdquo; exposure.\u003c/p\u003e\u003cp\u003eImportantly, our data suggest that institutional practices\u0026mdash;rather than patient characteristics alone\u0026mdash;may drive much of the observed variation. For instance, Facility D had significantly lower exposure rates and cumulative doses compared to Facilities B and G, despite caring for similarly preterm populations. This suggests opportunities for quality improvement and standardization of pain management protocols. Facilities with lower exposure may serve as models for effective, lower-risk approaches to sedation and analgesia.\u003c/p\u003e\u003cp\u003eOur study further adds to the limited literature evaluating polypharmacy in the NICU. The high rate of co-exposure to opioids and benzodiazepines (especially among those receiving\u0026thinsp;\u0026ge;\u0026thinsp;30 MME/kg) underscores the need to consider cumulative sedative burden. This variation in practice is concerning given the potential for neurotoxic effects of both drug classes. Benzodiazepines have been implicated in hippocampal growth abnormalities and impaired neurocognitive outcomes.\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e Although use of adjunctive agents like dexmedetomidine, ketamine, and propofol was infrequent, their increased use in neonates with high opioid exposure suggests a trend toward polypharmacy in the sickest patients. Although these newer agents may offer advantages such as reduced respiratory depression or neuroprotection in animal models, data on safety and efficacy in preterm neonates is extremely limited.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Our findings point to an urgent need for comparative effectiveness trials that evaluate both short-term safety and efficacy and longer-term neurodevelopmental outcome. Studies need to focus on these long-term neurodevelopmental outcomes, particularly higher-order cognitive functions like memory, attention, and executive functioning. These skills develop later in childhood and are more sensitive to subtle brain injuries.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe association between high cumulative opioid exposure and severe intraventricular hemorrhage, mechanical ventilation, vasoactive agents, and bronchopulmonary dysplasia observed in our cohort raises questions about causality versus confounding. It is plausible that neonates with these interventions or complications experience more pain and agitation, necessitating more pharmacologic interventions. However, opioid exposure itself has been shown to lower blood pressure, disrupt cerebral autoregulation, reduce cortical perfusion, and impair cerebellar growth which could exacerbate the risk of brain injury.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Future studies integrating real-time neuroimaging and pain scoring may help delineate whether opioid exposure contributes to brain injury or is a marker of illness severity.\u003c/p\u003e\u003cp\u003eSeveral limitations of our study must be acknowledged. First, the retrospective nature of exposure assessment may not fully capture every change in dosing or the concurrent use of non-pharmacologic pain interventions. Second, while we calculated MME and LME per kilogram, we did not analyze pharmacokinetics or cumulative plasma concentrations, which may vary significantly across neonates. Third, the lack of neurodevelopmental outcome data precludes direct assessment of long-term consequences, though our findings align with studies that do report such outcomes. Despite these limitations, our study provides a valuable real-world snapshot of opioid and benzodiazepine use in a diverse cohort of preterm neonates. It identifies key patient and facility-level drivers of exposure and highlights areas for potential stewardship and quality improvement. Institutions with lower exposure rates may serve as models for protocols that balance effective pain management with minimizing neurotoxic risk.\u003c/p\u003e\u003cp\u003eIn conclusion, our study highlights the widespread and variable use of opioids and benzodiazepines in extremely preterm neonates, particularly among those with greater illness severity. Given the growing evidence of potential neurotoxicity, there is a pressing need to standardize pain management practices, reduce unnecessary exposure, and rigorously evaluate long-term outcomes. Future research should focus on identifying optimal dosing strategies, integrating multimodal analgesia, and developing individualized, risk-informed approaches to sedation in this vulnerable population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments and Funding Disclosure:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunded in part by a grant from the US Food and Drug Administration U01FD007702.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the:\u003c/p\u003e\n\u003cp\u003e1. Conception and design of the work\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. The acquisition, analysis, and interpretation of data\u003c/p\u003e\n\u003cp\u003e3. Drafting the work and reviewing it critically for important intellectual content\u003c/p\u003e\n\u003cp\u003e4. Final approval of the version to be published\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCarbajal R, Rousset A, Danan C, et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA 2008;300:60\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCommittee on the Fetus and Newborn, Section on Pain, Prevention, and Management of Procedural Pain in the Neonate: An Update. Pediatrics 2016;137:e20154271.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSmith GC, Gutovich J, Smyser C, et al. Neonatal intensive care unit stress is associated with brain development in preterm infants. Ann Neurol 2011;70:541\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrummelte S, Grunau RE, Chau V, et al. Procedural pain and brain development in premature newborns. Ann Neurol 2012;71:385\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBouza H. The impact of pain in the immature brain. J Matern Fetal Neonatal Med 2009;22:722\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDoesburg SM, Chau CM, Cheung TPL, et al. Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age. Pain 2013;154:1946\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcPherson C, Miller SP, El-Dib M, Massaro AN, Inder TE. The influence of pain, agitation, and their management on the immature brain. Pediatr Res 2020;88:168\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSelvanathan T, Ufkes S, Guo T, et al. Pain exposure and brain connectivity in preterm infants. JAMA Netw Open 2024;7:e242551.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLim Y, Godambe S. Prevention and management of procedural pain in the neonate: an update, American Academy of Pediatrics, 2016. Arch Dis Child Educ Pract Ed 2017;102:254\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZwicker JG, Miller SP, Grunau RE, et al. Smaller cerebellar growth and poorer neurodevelopmental outcomes in very preterm infants exposed to neonatal morphine. J Pediatr 2016;172:81\u0026ndash;87 e2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcPherson C, Haslam M, Pineda R, Rogers C, Neil JJ, Inder TE. Brain injury and development in preterm infants exposed to fentanyl. Ann Pharmacother 2015;49:1291\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSelvanathan T, Zaki P, McLean MA, et al. Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants. Pediatr Res 2023;94:738\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePuia-Dumitrescu M, Comstock BA, Li S, et al. Assessment of 2-year neurodevelopmental outcomes in extremely preterm infants receiving opioids and benzodiazepines. JAMA Netw Open 2021;4:e2115998.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKocek M, Wilcox R, Crank C, Patra K. Evaluation of the relationship between opioid exposure in extremely low birth weight infants in the neonatal intensive care unit and neurodevelopmental outcome at 2 years. Early Hum Dev 2016;92:29\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSteinbauer P, Deindl P, Fuiko R, et al. Long-term impact of systematic pain and sedation management on cognitive, motor, and behavioral outcomes of extremely preterm infants at preschool age. Pediatr Res 2021;89:540\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMills KP, Lean RE, Smyser CD, Inder T, Rogers C, McPherson CC. Fentanyl exposure in preterm infants: Five-year neurodevelopmental and socioemotional assessment. Front Pain Res (Lausanne) 2022;3:836705.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGiordano V, Deindl P, Fuiko R, et al. Effect of increased opiate exposure on three years neurodevelopmental outcome in extremely preterm infants. Early Hum Dev 2018;123:1\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYoung C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and midazolam, individually or in combination, to induce apoptotic neurodegeneration in the infant mouse brain. 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Use of analgesic and sedative drugs in VLBW infants in German NICUs from 2003\u0026ndash;2010. Eur J Pediatr 2013;172:1633\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCarbajal R, Eriksson M, Courtois E, et al. Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study. Lancet Respir Med 2015;3:796\u0026ndash;812.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBorenstein-Levin L, Synnes A, Grunau RE, et al. Narcotics and sedative use in preterm neonates. J Pediatr 2017;180:92\u0026thinsp;\u0026ndash;\u0026thinsp;8 e1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchiller RM, Allegaert K, Hunfeld M, van den Bosch GE, van den Anker J, Tibboel D. Analgesics and sedatives in critically ill newborns and infants: The impact on long-term neurodevelopment. J Clin Pharmacol 2018;58 Suppl 10:S140-50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavidson A, Flick RP. Neurodevelopmental implications of the use of sedation and analgesia in neonates. Clin Perinatol 2013;40:559\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWalter-Nicolet E, Marchand-Martin L, Morgan AS, et al. Neurodevelopmental outcomes at five years in children born very preterm (24\u0026ndash;31 weeks) exposed to opioids with or without midazolam: results from the French nationwide EPIPAGE-2 cohort study. Lancet Reg Health Eur 2025;52:101242.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDuerden EG, Guo T, Dodbiba L, et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann Neurol 2016;79:548\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcPherson C, Grunau RE. 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Clin Perinatol 2014;41:209\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7105002/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7105002/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e To quantify opioid and benzodiazepine exposure in extremely preterm neonates and assess variation by gestational age, facility, and clinical factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design:\u003c/strong\u003e 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e 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).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Opioid and benzodiazepine use is common and variable in extremely preterm neonates. Standardized pain management and long-term outcome studies are urgently needed.\u003c/p\u003e","manuscriptTitle":"Cumulative Exposure to Opioids and Benzodiazepines in Extremely Preterm Neonates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 14:59:15","doi":"10.21203/rs.3.rs-7105002/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-08-18T19:09:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-08-07T15:35:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-07-31T16:57:52+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-07-15T16:01:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-14T12:46:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-12T01:05:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2025-07-12T01:05:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b5f4a2e6-2ae2-4235-be41-9e1d897ae54c","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51710710,"name":"Health sciences/Medical research/Outcomes research"},{"id":51710711,"name":"Health sciences/Medical research/Epidemiology"}],"tags":[],"updatedAt":"2025-11-28T08:24:44+00:00","versionOfRecord":{"articleIdentity":"rs-7105002","link":"https://doi.org/10.1038/s41372-025-02513-9","journal":{"identity":"journal-of-perinatology","isVorOnly":false,"title":"Journal of Perinatology"},"publishedOn":"2025-11-27 05:00:00","publishedOnDateReadable":"November 27th, 2025"},"versionCreatedAt":"2025-07-18 14:59:15","video":"","vorDoi":"10.1038/s41372-025-02513-9","vorDoiUrl":"https://doi.org/10.1038/s41372-025-02513-9","workflowStages":[]},"version":"v1","identity":"rs-7105002","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7105002","identity":"rs-7105002","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}