Prolonged Hyperoxia Exposure is an Independent Predictor for Moderate to Severe Neurodevelopmental Impairment in Extremely Premature Neonates

Prolonged Hyperoxia Exposure is an Independent Predictor for Moderate to Severe Neurodevelopmental Impairment in Extremely Premature 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 Prolonged Hyperoxia Exposure is an Independent Predictor for Moderate to Severe Neurodevelopmental Impairment in Extremely Premature Neonates Thu Tran, Navya Sankoorikkal, Lyca Intal, Thomas Lu, Saef Munir, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7428681/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Retrospective cohort study of extremely preterm infants (< 28 weeks’ gestational age and birth weight ≤ 1500 g) treated at a level IV academic hospital from January 2008 to July 2018 to assess if prolonged hyperoxia is an independent risk factor for severe neurodevelopmental impairment (NDI) or death. Among 546 former extremely preterm infants, 327 (59.9%) were exposed to prolonged hyperoxia. Prolonged hyperoxia was associated with increased odds of severe NDI or death (OR 1.77, 95% CI 1.01 to 3.14) after adjusting for risk factors. When the components of the primary outcome were analyzed separately, prolonged hyperoxia was not associated with severe NDI among survivors (OR 1.39, 95% CI 0.74 to 2.63) but was associated with death (OR 3.20, 95% CI 1.23 to 9.59). In conclusion, prolonged exposure to oxygen is a significant and independent risk factor for development of long-term moderate to severe NDI including death. Health sciences/Risk factors Health sciences/Diseases/Neurological disorders/Neurodevelopmental disorders Hyperoxia neurodevelopmental impairment extremely premature neonates Figures Figure 1 Introduction Extremely premature neonates, born less than 28 weeks of gestation, face a high risk of respiratory distress syndrome due to surfactant deficiency( 1 ). Lack of alveolar differentiation and surfactant synthesis by type II pneumocytes impair critical gas exchange, and many preterm neonates require mechanical ventilation after birth to meet oxygen demands( 2 , 3 ). Premature infants are particularly vulnerable to free oxygen radicals due to an immature antioxidant defense system. This leads to oxidative stress, resulting in DNA damage, systemic inflammation, impaired lung development, and alveolar hypoplasia – the underlying factors in the development of bronchopulmonary dysplasia (BPD)( 4 ). BPD affects approximately 43% of babies delivered before 29 weeks of gestation with mortality and long-term morbidities including neurodevelopmental impairment (NDI)( 5 – 7 ). Delayed neurodevelopment is often attributed to prolonged intubation required for managing BPD. Few studies have investigated the effects of hyperoxia on neurodevelopmental outcomes in extremely premature neonates ( 5 , 8 , 9 ). We hypothesize that prolonged exposure to excessive oxygen concentration in the preterm infant is an independent risk factor for moderate to severe NDI. Methods PATIENT POPULATION Eligible infants for this retrospective cohort study were extremely premature newborns (< 28 weeks’ gestational age and birth weight ≤ 1500 grams) admitted at Children’s Memorial Hermann Hospital, Houston, Texas, from January 2008 to July 2018. Study was approved by institutional review board with waiver of consent. Infants that were delivered at another facility and transferred to Children’s Memorial Hermann Hospital after one day of age or had early demise before three days of age were excluded due to limited and incomplete data. To minimize potential confounding in neurodevelopmental outcomes, infants with syndromic genetic conditions or other major congenital anomalies were also excluded from the study. EXPOSURE Prolonged exposure to hyperoxia was defined as receiving fraction of inspired oxygen (FiO 2 ) ≥ 0.4, delivered via non-invasive or invasive positive pressure ventilation, for a cumulative duration of at least three days. Positive pressure ventilation included high flow nasal cannula (HFNC), nasal continuous positive pressure airway pressure (nCPAP), or invasive mechanical ventilation. FiO 2 administration was titrated by the bedside nurse to target peripheral oxygen saturation (SpO 2 ) of 85–95% measured by continuous pulse oximetry during the study period. OUTCOME Bayley Scales of Infant and Toddler Development exam was conducted at 22–26 months of corrected age to assess for NDI in the outpatient clinic by trained clinical psychologists. The second edition (Bayley II Mental Development Index) was used from 2008 to 2016 and the third edition (Bayley III) from 2016 to 2018 for NDI assessment. Moderate to severe NDI was defined as Bayley II Mental Developmental Index (MDI) below 70 or Bayley III cognitive score below 85, criteria that have demonstrated 97% concordance in prior studies( 10 , 11 ). For the purposes of this study, details on cerebral palsy, motor function, blindness, or deafness were not included in our assessment. DATA ANALYSIS Continuous variables were summarized using means and standard deviations (SD). Categorical variables were summarized using frequencies and percentages. Two-tailed Student’s t test and chi-squared test were used to compare maternal and neonatal characteristics between hyperoxia and non-hyperoxia exposed groups. The primary outcome was severe NDI or death treated as a binary variable. With a sample size of 546 and a ratio of hyperoxia to non-hyperoxia of 1.5, we are powdered to detect an odds ratio (OR) as low as 1.6 with a power of 80% and an alpha level of 0.05, using a Chi-squared test. A common rule of thumb for sample size in multivariable logistic regression is to have at least ten observations in the least common outcome category for each variable included in the model. Thus, the sample size in the study was adequate for both the univariable and the multivariable analyses. Multivariable logistic regression analysis was used to determine if hyperoxia was an independent predictor of NDI or death after adjusting for baseline characteristics and co-morbidities including severe intraventricular hemorrhage (IVH) of grade 3 to 4, diagnosis of necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and BPD defined using Jensen’s criteria( 12 ). Jensen’s criteria assess neonates at 36 weeks’ postmenstrual age and classify the severity of BPD as follows: Grade 1 (mild) for those receiving ≤ 2 L/min of flow via nasal cannula, Grade 2 (moderate) for those requiring ≥ 2 L/min of flow via nasal cannula or non-invasive positive airway pressure, and Grade 3 (severe) for those requiring invasive mechanical ventilation( 12 ). Those not on oxygen supplementation at 36 weeks’ postmenstrual age were classified as having no BPD( 12 ). In addition, mean airway pressure (MAP) greater than 10 cmH 2 0 was used to adjust for severity of lung disease( 13 , 14 ). The same model was used to evaluate the relationship of hyperoxia and the individual components of the primary outcome. Statistical significance was defined as a p-value ≤ 0.05. All statistical analyses were performed in R Statistical Software (version 4.2.0; R Core Team 2022). Results From January 2008 to July 2018, a total of 635 infants met the inclusion criteria of inborn extremely preterm infants that survived at least three days of life. Of these infants, 89 were excluded due to missing Bayley MDI assessments. A remaining total of 546 infants had Bayley assessments conducted at 22–26 months corrected age. Four infants in the non-hyperoxia exposed group were excluded in the logistic regression analysis due to missing method of oxygen delivery. PRIMARY OUTCOME Among the study cohort, 327 (59.8%) extremely preterm neonates were exposed to prolonged hyperoxia (Fig. 1). Prolonged exposure to hyperoxia in the extremely preterm population was a significant independent risk factor for moderate and severe NDI or death after adjusting for risk factors including gestational age and other co-morbidities (OR 1.77, 95% CI 1.01–3.14) (Tables 1 and 2 ). When the components of the primary outcome were analyzed separately, prolonged hyperoxia was not significantly associated with severe NDI among survivors (OR 1.39, 95% CI 0.74 to 2.63) (Table 2 ) but was significantly associated with death (OR 3.20, 95% CI 1.23 to 9.59). Table 1 Baseline characteristics Characteristics No Hyperoxia (N = 215) Hyperoxia (N = 327) P-value Maternal Maternal Age – yr 28.7 ± 7.1 29.2 ± 7.0 0.490 Race or ethnic group – no. (%) White/ Caucasian 43 (20.0) 82 (25.1) 0.170 North American Indian/ Native Alaskan) 0 (0) 1 (0.3) 0.417 Asian 4 (1.9) 5 (1.5) 0.768 Black/African American 102 (47.4) 133 (40.7) 0.120 Native Hawaiian/Other Pacific Islander 0 (0) 0 (0) Other 64 (29.8) 107 (32.) 0.469 Maternal hypertension – no. (%) 34 (16.1) 75 (23.1) 0.048* Maternal diabetes – no. (%) 9 (4.3) 18 (5.6) 0.505 Intraamniotic Infection – no. (%) 57 (26.5) 80 (24.7) 0.635 Adequate antenatal glucocorticoid (≥ 2 doses – no. (%) 139 (65.3) 179 (55.4) 0.023* Caesarean Section 141 (65.6) 231 (70.6) 0.214 Multiple birth – no. (%) 40 (18.7) 75 (23.4) 0.197 Prolonged rupture of membrane > 18 hrs – no. (%) 63 (29.4) 104 (32.1) 0.514 Neonatal Gestational Age – wk 25.5 ± 0.9 24.7 ± 1.0 < 0.001* Male sex – no. (%) 161 (48.6) 123 (57.2) 0.050* Mean birth weight (range) -- g 788 (403–1370) 668 (330–1115) < 0.001* Mean APGAR at 5 mins (range) 6 ( 1 – 9 ) 5 (0–10) < 0.001* †Four subjects had missing hyperoxia status. *Denotes statistical significance Table 2 Multivariable Regression Model for Neurodevelopmental Impairment (NDI) Risk Factors/ Comorbidities No NDI (N = 331) NDI (N = 215) Adjusted OR (95% CI) P -value Hyperoxia Exposure No Hyperoxia 156 (47.7%) 59 (27.4%) Reference -- Hyperoxia 171 (52.3%) 156 (72.6%) 1.77 (1.01–3.14) 0.048* Gestational Age (weeks) ≤ 24 41 (12.4%) 82 (38.1%) Reference -- 24–25 102 (30.8%) 71 (33.0%) 0.94 (0.51–1.74) 0.84 25–26 104 (31.4%) 40 (18.6%) 0.54 (0.27–1.08) 0.08 26–27 84 (25.4%) 22 (10.2%) 0.55 (0.24–1.24) 0.16 Gender Female 170 (51.4%) 92 (42.8%) Reference -- Male 161 (48.6%) 123 (57.2%) 1.38 (0.87–2.18) 0.17 Intraventricular Hemorrhage (IVH) Not Severe (Grade 1–2) 318 (96.1%) 159 (74.0%) Reference -- Severe (Grade 3–4) 13 (3.9%) 56 (26.0%) 4.76 (2.23–10.80) < 0.001* Necrotizing Enterocolitis (NEC) No NEC 312 (94.3%) 176 (81.9%) Reference -- NEC Present 19 (5.7%) 39 (18.1%) 2.96 (1.48–5.98) 0.002* Retinopathy of Prematurity (ROP) No ROP 297 (91.4%) 117 (76.5%) Reference -- ROP Present 28 (8.6%) 36 (23.5%) 2.26 (1.20–4.25) 0.011* Bronchopulmonary Dysplasia (BPD) None, Mild or Moderate 136 (45.8%) 30 (15.7%) Reference -- Severe 161 (54.2%) 161 (84.3%) 1.41 (0.79–2.52) 0.25 Mean Airway Pressure (MAP) None or Low (< 10 cm H 2 O) 306 (92.4%) 177 (83.5%) Medium or High (≥ 10 cm H 2 O) 25 (7.6%) 35 (16.5%) 1.50 (0.73–3.05) 0.26 *Denotes statistical significance ≤ 0.05. Reference group used for subgroup analysis indicated within table. SECONDARY OUTCOME In this cohort, IVH (OR 4.76, 95% CI 2.23–10.80), NEC (OR 2.96, 95% CI 1.48–5.88) and ROP (OR 2.26, 95% CI 1.20–4.25) was associated with increased odds of NDI or death when controlling for hyperoxia exposure and other baseline characteristics. Patients with severe BPD did not have increased odds of NDI (OR 1. 41, 95% CI 0.79–2.52) (Table 2 ). Gestational age, sex, and high MAP (> 10 cmH 2 0) were not significant independent risk factors for NDI or death (Table 2 ). However, utilizing subgroup analysis for survivors only, severe IVH (OR 3.75, 95% CI 1.58–9.16) and ROP (OR 2.63, 95% CI 1.32–5.22) remained significant risk factors for NDI or death (Table 3 ). Table 3 Multivariable Regression Model for Neurodevelopmental Impairment (NDI) Among Survivors Risk Factors/ Comorbidities No NDI (N = 331) NDI (N = 100) Adjusted OR (95% CI) P -value Hyperoxia Exposure No Hyperoxia 156 (47.7%) 28 (28.0%) Reference -- Hyperoxia 171 (52.3%) 72 (72.0%) 1.39 (0.74–2.63) 0.31 Gestational Age (weeks) ≤ 24 41 (12.4%) 26 (26.0%) Reference -- 24–25 102 (30.8%) 34 (34.0%) 0.86 (0.43–1.76) 0.68 25–26 104 (31.4%) 28 (28.0%) 0.60 (0.28–1.30) 0.19 26–27 84 (25.4%) 12 (12.0%) 0.48 (0.18–1.23) 0.13 Gender Female 170 (51.4%) 37 (37.0%) Reference -- Male 161 (48.6%) 63 (63.0%) 1.38 (0.91–2.59) 0.11 Intraventricular Hemorrhage (IVH) Not Severe (Grade 1–2) 318 (96.1%) 84 (84.0%) Reference -- Severe (Grade 3–4) 13 (3.9%) 16 (16.0%) 3.75 (1.58–9.16) 0.003* Necrotizing Enterocolitis (NEC) No NEC 312 (94.3%) 86 (86.0%) Reference -- NEC Present 19 (5.7%) 14 (14.0%) 1.77 (0.74–4.06) 0.19 Retinopathy of Prematurity (ROP) No ROP 297 (91.4%) 72 (73.5%) Reference -- ROP Present 28 (8.6%) 26 (26.5%) 2.63 (1.32–5.22) 0.006* Bronchopulmonary Dysplasia (BPD) None, Mild or Moderate 136 (45.8%) 22 (23.7%) Reference -- Severe 161 (54.2%) 71 (76.3%) 1.28 (0.66–2.51) 0.47 Mean Airway Pressure (MAP) None or Low (< 10 cm H 2 O) 306 (92.4%) 83 (83.0%) Medium or High (≥ 10 cm H 2 O) 25 (7.6%) 17 (17.0%) 1.85 (0.84–4.01) 0.12 *Denotes statistical significance ≤ 0.05. Reference group used for subgroup analysis indicated within table. Discussion Our study aimed to investigate if prolonged hyperoxia exposure was independently associated with severe NDI or death. Our findings provide supporting evidence that infants requiring FiO 2 ≥ 0.4 for cumulative duration of at least three days have significantly increased odds of NDI or death. Optimal oxygen saturation (SpO 2 ) in preterm infants is still under debate. Three large clinical studies including Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT), Benefits of Oxygen Saturation Targeting (BOOST) II and Canadian Oxygen Trial (COT) investigated lower versus higher SpO 2 target range in preterm infants less than 28 weeks’ gestational age. The SUPPORT trial found that lower SpO 2 target range of 85–89% increased risk of death before discharge compared to SpO 2 target range of 91–95%, but overall mortality rates or NDI at 18 to 22 months’ corrected age were no different( 15 ) − ( 16 ). The BOOST II trial also demonstrated increased mortality rates in the lower SpO 2 group after changing their methodology for technical oximeter-calibration during their trial( 17 ). The COT trial found no difference in death or NDI at 18 months’ corrected age ( 18 ). A Cochrane review that included late preterm infants found oxygen administration and oxygen target range did not have significant effect on mortality, but liberal oxygen administration had a significant increased risk for combined adverse outcome of death or retrolental fibroplasia( 19 ). In the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) that included the above-mentioned studies, lower SpO2 target range of 85%-95% increased risk for death and NEC, but showed no difference in NDI( 20 ). A recent retrospective observational study of preterm neonates born less than 28 weeks’ gestational age found that white matter injury of the brain was more prevalent in neonates with lower targeted SpO 2 (less than 90%) on magnetic resonance imaging (MRI), as well as in those with longer accumulated days requiring FiO 2 greater than 0.21. These factors were also associated with poorer neurodevelopmental assessment scores( 21 ). Supporting clinical studies, animal models have further demonstrated the detrimental impact of hyperoxia on brain injury, highlighting the potential mechanisms underlying neurological damage in premature neonates. During the infantile period, animals subjected to hyperoxia had brain injury due to various proposed mechanisms such as neuronal apoptosis, reduced brain mass, mitochondrial dysfunction, neurotrophin protection downregulation, reactive oxygen species (ROS) accumulation, inflammation-induced myelination disruption, as well as impairment of the axon-oligodendrocyte integrity and neuronal plasticity ( 21 – 29 ). In vitro MRI imaging and histochemical analysis of brain tissue in mice exposed to FiO 2 > 85% for 14 days revealed reduced hippocampal and cerebellar volume as well as associated impaired spatial and recognition memory ( 17 ). Multiple animal studies have investigated the effects of prolonged hyperoxia on brain development, but there is a large variation in the animal model used as well as the degree of hyperoxia exposure ( 30 – 32 ). Clinical studies have predominantly focused on BPD as a risk factor for poor neurodevelopmental outcomes. However, to the authors’ knowledge, none have examined prolonged cumulative exposure to FiO 2 ≥ 0.40 as an independent risk factor ( 7 , 33 – 35 ). There are several limitations to our study. First, this is a retrospective review and data on the corresponding SpO 2 at the time of FiO2 administration was unavailable which could limit the direct correlation between patient saturation and supplemental oxygen titration. We acknowledge the lack of concurrent SpO 2 data may cause difficulties in identifying critically ill patients that may need higher supplemental oxygen support. Our neonatal intensive care unit follows a protocol to keep SpO 2 target range between 90–95% for premature infants. Additionally, SpO 2 values alone do not capture the severity of lung disease. To address this limitation, MAP values were incorporated to account for the degree of lung severity and overall clinical illness. Another limitation is FiO 2 levels is not a direct measure of O 2 delivery to tissues. Although measured arterial oxygen levels would provide a more accurate assessment of whether FiO 2 administration was excessive, the limited availability of arterial blood gas values constrained their use in this study. Lastly, in our patient population, there was a high mortality rate in the hyperoxia group. This introduces a potential bias, as death itself may have a more significant impact on outcomes than hyperoxia, potentially confounding the interpretation of the relationship between hyperoxia and clinical outcomes. Lastly, many infant deaths occurred in the hyperoxia group, and separating the mortality group from the hyperoxia group would have significantly reduced our sample size. As a result, both groups were included in our primary analysis. Conclusion In conclusion, oxygen is a critical therapy in the management of extremely premature infants born under 28 weeks’ gestational age, but prolonged and excessive exposure to oxygen may be a significant and independent risk factor for development of long-term moderate to severe NDI including death. Our study adds to current literature by focusing on the administration of supplemental oxygen via positive pressure ventilation in preterm neonates and its association with death and adverse neurodevelopmental outcomes. Declarations Conflict of Interest: The authors have no conflicts of interest to declare. Ethics Statement: Data retrieval and review were approved by McGovern Medical School at the University of Texas Health Science Center at Houston IRB review board (HSC-MS21-0335). Consent waived as this is a retrospective review. Funding: TF is supported by KL2 TR003168, UL1 TR003167. WL is partly supported by UL1TR003167. TT is supported by T32 5T32GM135118 Author Contributions: TTT and TF responsible for conceptualization and revision of paper. NS, LI, TL, SM and AJ carried out data acquisition. TTT, WL, AFC, AK and TF analyzed and interpreted data. Data Availability Statement: Data published in article can be made available via request. References Sardesai S, Biniwale M, Wertheimer F, Garingo A, Ramanathan R. Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future. Pediatr Res. 2017;81(1–2):240–8. Nkadi PO, Merritt TA, Pillers DA. An overview of pulmonary surfactant in the neonate: genetics, metabolism, and the role of surfactant in health and disease. Mol Genet Metab. 2009;97(2):95–101. Cannavò L, Perrone S, Viola V, Marseglia L, Di Rosa G, Gitto E. Oxidative Stress and Respiratory Diseases in Preterm Newborns. Int J Mol Sci. 2021;22(22). Auten RL, Davis JM. Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details. 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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-7428681","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":504634417,"identity":"f0563118-972c-4d1d-82ab-29f4b668c714","order_by":0,"name":"Thu Tran","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYDACCSjNz8DABhMzwKuDB6TlABBLNjADtSSQosXgALFa7KV7DJg/7rHLM76Rf+wB449t8gzszdsk8GnhkTljwHDgWXKx2Y1kdgOGhNuGDTzHyvBrkcgBajnAnLjtRjKbBFBLAoNEjhkxWuoTN8+AaZF/Q5SWw4kbJOC28BDQciOt4MCZA8cTZ5x5bCaRkHbbsI0nrdgCnxb2GckbH1QcqE7sb098JvHB5rY8P/vhjTfwaQGBA3BWAgNSGhgFo2AUjIJRQD4AALejROm993dqAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-4875-7438","institution":"McGovern Medical School at UTHealth Houston","correspondingAuthor":true,"prefix":"","firstName":"Thu","middleName":"","lastName":"Tran","suffix":""},{"id":504634418,"identity":"a5696230-0b81-4152-939a-5e482c1fad8c","order_by":1,"name":"Navya Sankoorikkal","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Navya","middleName":"","lastName":"Sankoorikkal","suffix":""},{"id":504634419,"identity":"03da64ef-a047-4b3d-8f31-11e4e1768b5d","order_by":2,"name":"Lyca Intal","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lyca","middleName":"","lastName":"Intal","suffix":""},{"id":504634420,"identity":"2e2653bd-f47f-48d1-90f1-106db01977bb","order_by":3,"name":"Thomas Lu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Lu","suffix":""},{"id":504634421,"identity":"1bed516f-66bd-4d1c-97ca-a6e0c0d8f961","order_by":4,"name":"Saef Munir","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Saef","middleName":"","lastName":"Munir","suffix":""},{"id":504634422,"identity":"af5acc7f-183f-40f4-b6dd-8d92153c8cea","order_by":5,"name":"Aman Jain","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Aman","middleName":"","lastName":"Jain","suffix":""},{"id":504634423,"identity":"28e9ea79-4ae1-4317-9529-5b42e7bf361a","order_by":6,"name":"Wen Li","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Li","suffix":""},{"id":504634424,"identity":"a718ff62-0f75-4dba-9207-245989ef8bef","order_by":7,"name":"Antonio Corno","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Corno","suffix":""},{"id":504634425,"identity":"118f977e-70fc-4d16-ba15-6fa820964767","order_by":8,"name":"Amir Khan","email":"","orcid":"","institution":"University of Texas-Houston Medical School","correspondingAuthor":false,"prefix":"","firstName":"Amir","middleName":"","lastName":"Khan","suffix":""},{"id":504634426,"identity":"78eb8ac8-7f47-4a19-ad8e-360cdcc9892a","order_by":9,"name":"Tina Findley","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Tina","middleName":"","lastName":"Findley","suffix":""}],"badges":[],"createdAt":"2025-08-21 18:35:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7428681/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7428681/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90317197,"identity":"78d89550-c343-4246-a851-cd3abd840ccd","added_by":"auto","created_at":"2025-09-01 10:26:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47937,"visible":true,"origin":"","legend":"\u003cp\u003eStudy cohort and outcomes\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7428681/v1/56a7ad24a907903c9a83c4ab.png"},{"id":91877151,"identity":"ab3b4a56-5e79-4e19-832c-48209d8739af","added_by":"auto","created_at":"2025-09-22 14:38:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":974752,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7428681/v1/40ebe0de-4a59-4258-9837-aac1852fd8dd.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Prolonged Hyperoxia Exposure is an Independent Predictor for Moderate to Severe Neurodevelopmental Impairment in Extremely Premature Neonates","fulltext":[{"header":"Introduction","content":"\u003cp\u003eExtremely premature neonates, born less than 28 weeks of gestation, face a high risk of respiratory distress syndrome due to surfactant deficiency(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Lack of alveolar differentiation and surfactant synthesis by type II pneumocytes impair critical gas exchange, and many preterm neonates require mechanical ventilation after birth to meet oxygen demands(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Premature infants are particularly vulnerable to free oxygen radicals due to an immature antioxidant defense system. This leads to oxidative stress, resulting in DNA damage, systemic inflammation, impaired lung development, and alveolar hypoplasia \u0026ndash; the underlying factors in the development of bronchopulmonary dysplasia (BPD)(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBPD affects approximately 43% of babies delivered before 29 weeks of gestation with mortality and long-term morbidities including neurodevelopmental impairment (NDI)(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Delayed neurodevelopment is often attributed to prolonged intubation required for managing BPD. Few studies have investigated the effects of hyperoxia on neurodevelopmental outcomes in extremely premature neonates (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). We hypothesize that prolonged exposure to excessive oxygen concentration in the preterm infant is an independent risk factor for moderate to severe NDI.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePATIENT POPULATION\u003c/h2\u003e\u003cp\u003eEligible infants for this retrospective cohort study were extremely premature newborns (\u0026lt;\u0026thinsp;28 weeks\u0026rsquo; gestational age and birth weight\u0026thinsp;\u0026le;\u0026thinsp;1500 grams) admitted at Children\u0026rsquo;s Memorial Hermann Hospital, Houston, Texas, from January 2008 to July 2018. Study was approved by institutional review board with waiver of consent. Infants that were delivered at another facility and transferred to Children\u0026rsquo;s Memorial Hermann Hospital after one day of age or had early demise before three days of age were excluded due to limited and incomplete data. To minimize potential confounding in neurodevelopmental outcomes, infants with syndromic genetic conditions or other major congenital anomalies were also excluded from the study.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEXPOSURE\u003c/h3\u003e\n\u003cp\u003eProlonged exposure to hyperoxia was defined as receiving fraction of inspired oxygen (FiO\u003csub\u003e2\u003c/sub\u003e)\u0026thinsp;\u0026ge;\u0026thinsp;0.4, delivered via non-invasive or invasive positive pressure ventilation, for a cumulative duration of at least three days. Positive pressure ventilation included high flow nasal cannula (HFNC), nasal continuous positive pressure airway pressure (nCPAP), or invasive mechanical ventilation. FiO\u003csub\u003e2\u003c/sub\u003e administration was titrated by the bedside nurse to target peripheral oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e) of 85\u0026ndash;95% measured by continuous pulse oximetry during the study period.\u003c/p\u003e\n\u003ch3\u003eOUTCOME\u003c/h3\u003e\n\u003cp\u003eBayley Scales of Infant and Toddler Development exam was conducted at 22\u0026ndash;26 months of corrected age to assess for NDI in the outpatient clinic by trained clinical psychologists. The second edition (Bayley II Mental Development Index) was used from 2008 to 2016 and the third edition (Bayley III) from 2016 to 2018 for NDI assessment. Moderate to severe NDI was defined as Bayley II Mental Developmental Index (MDI) below 70 or Bayley III cognitive score below 85, criteria that have demonstrated 97% concordance in prior studies(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). For the purposes of this study, details on cerebral palsy, motor function, blindness, or deafness were not included in our assessment.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eDATA ANALYSIS\u003c/h2\u003e\u003cp\u003eContinuous variables were summarized using means and standard deviations (SD). Categorical variables were summarized using frequencies and percentages. Two-tailed Student\u0026rsquo;s t test and chi-squared test were used to compare maternal and neonatal characteristics between hyperoxia and non-hyperoxia exposed groups. The primary outcome was severe NDI or death treated as a binary variable. With a sample size of 546 and a ratio of hyperoxia to non-hyperoxia of 1.5, we are powdered to detect an odds ratio (OR) as low as 1.6 with a power of 80% and an alpha level of 0.05, using a Chi-squared test. A common rule of thumb for sample size in multivariable logistic regression is to have at least ten observations in the least common outcome category for each variable included in the model. Thus, the sample size in the study was adequate for both the univariable and the multivariable analyses. Multivariable logistic regression analysis was used to determine if hyperoxia was an independent predictor of NDI or death after adjusting for baseline characteristics and co-morbidities including severe intraventricular hemorrhage (IVH) of grade 3 to 4, diagnosis of necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and BPD defined using Jensen\u0026rsquo;s criteria(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Jensen\u0026rsquo;s criteria assess neonates at 36 weeks\u0026rsquo; postmenstrual age and classify the severity of BPD as follows: Grade 1 (mild) for those receiving\u0026thinsp;\u0026le;\u0026thinsp;2 L/min of flow via nasal cannula, Grade 2 (moderate) for those requiring\u0026thinsp;\u0026ge;\u0026thinsp;2 L/min of flow via nasal cannula or non-invasive positive airway pressure, and Grade 3 (severe) for those requiring invasive mechanical ventilation(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Those not on oxygen supplementation at 36 weeks\u0026rsquo; postmenstrual age were classified as having no BPD(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In addition, mean airway pressure (MAP) greater than 10 cmH\u003csub\u003e2\u003c/sub\u003e0 was used to adjust for severity of lung disease(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The same model was used to evaluate the relationship of hyperoxia and the individual components of the primary outcome. Statistical significance was defined as a p-value\u0026thinsp;\u0026le;\u0026thinsp;0.05. All statistical analyses were performed in R Statistical Software (version 4.2.0; R Core Team 2022).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFrom January 2008 to July 2018, a total of 635 infants met the inclusion criteria of inborn extremely preterm infants that survived at least three days of life. Of these infants, 89 were excluded due to missing Bayley MDI assessments. A remaining total of 546 infants had Bayley assessments conducted at 22\u0026ndash;26 months corrected age. Four infants in the non-hyperoxia exposed group were excluded in the logistic regression analysis due to missing method of oxygen delivery.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003ePRIMARY OUTCOME\u003c/h2\u003e\u003cp\u003eAmong the study cohort, 327 (59.8%) extremely preterm neonates were exposed to prolonged hyperoxia (Fig.\u0026nbsp;1). Prolonged exposure to hyperoxia in the extremely preterm population was a significant independent risk factor for moderate and severe NDI or death after adjusting for risk factors including gestational age and other co-morbidities (OR 1.77, 95% CI 1.01\u0026ndash;3.14) (Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). When the components of the primary outcome were analyzed separately, prolonged hyperoxia was not significantly associated with severe NDI among survivors (OR 1.39, 95% CI 0.74 to 2.63) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) but was significantly associated with death (OR 3.20, 95% CI 1.23 to 9.59).\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\u003eBaseline characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo Hyperoxia\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;215)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHyperoxia\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;327)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal Age \u0026ndash; yr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.7\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;7.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.2\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;7.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.490\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRace or ethnic group \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite/ Caucasian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82 (25.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.170\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNorth American Indian/ Native Alaskan)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.417\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (1.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (1.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.768\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlack/African American\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e102 (47.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e133 (40.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.120\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNative Hawaiian/Other Pacific Islander\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64 (29.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e107 (32.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.469\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal hypertension \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (16.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75 (23.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.048*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal diabetes \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (5.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.505\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntraamniotic Infection \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57 (26.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80 (24.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.635\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdequate antenatal glucocorticoid (\u0026ge;\u0026thinsp;2 doses \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e139 (65.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e179 (55.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.023*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCaesarean Section\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e141 (65.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e231 (70.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.214\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMultiple birth \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (18.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75 (23.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.197\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProlonged rupture of membrane\u0026thinsp;\u0026gt;\u0026thinsp;18 hrs \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e63 (29.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104 (32.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.514\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNeonatal\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGestational Age \u0026ndash; wk\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.5\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.7\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex \u0026ndash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e161 (48.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123 (57.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.050*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean birth weight (range) -- g\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e788 (403\u0026ndash;1370)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e668 (330\u0026ndash;1115)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean APGAR at 5 mins (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7 CR8\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (0\u0026ndash;10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u0026dagger;Four subjects had missing hyperoxia status.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003e*Denotes statistical significance\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\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\u003eMultivariable Regression Model for Neurodevelopmental Impairment (NDI)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRisk Factors/ Comorbidities\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo NDI\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;331)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNDI\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;215)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eHyperoxia Exposure\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo Hyperoxia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e156 (47.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e59 (27.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003e--\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHyperoxia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e171 (52.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e156 (72.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.77 (1.01\u0026ndash;3.14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.048*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGestational Age (weeks)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41 (12.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e82 (38.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u0026ndash;25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e102 (30.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71 (33.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.94 (0.51\u0026ndash;1.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25\u0026ndash;26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e104 (31.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40 (18.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.54 (0.27\u0026ndash;1.08)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u0026ndash;27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e84 (25.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (10.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.55 (0.24\u0026ndash;1.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e170 (51.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e92 (42.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e161 (48.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e123 (57.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.38 (0.87\u0026ndash;2.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIntraventricular Hemorrhage (IVH)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot Severe (Grade 1\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e318 (96.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e159 (74.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere (Grade 3\u0026ndash;4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56 (26.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.76 (2.23\u0026ndash;10.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNecrotizing Enterocolitis (NEC)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo NEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e312 (94.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e176 (81.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNEC Present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (5.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39 (18.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.96 (1.48\u0026ndash;5.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.002*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRetinopathy of Prematurity (ROP)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo ROP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e297 (91.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e117 (76.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eROP Present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (8.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (23.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.26 (1.20\u0026ndash;4.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.011*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBronchopulmonary Dysplasia (BPD)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNone, Mild or Moderate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e136 (45.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 (15.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e161 (54.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e161 (84.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.41 (0.79\u0026ndash;2.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean Airway Pressure (MAP)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNone or Low (\u0026lt;\u0026thinsp;10 cm H\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e306 (92.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e177 (83.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedium or High (\u0026ge;\u0026thinsp;10 cm H\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (7.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35 (16.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.50 (0.73\u0026ndash;3.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Denotes statistical significance\u0026thinsp;\u0026le;\u0026thinsp;0.05. Reference group used for subgroup analysis indicated within table.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSECONDARY OUTCOME\u003c/h3\u003e\n\u003cp\u003eIn this cohort, IVH (OR 4.76, 95% CI 2.23\u0026ndash;10.80), NEC (OR 2.96, 95% CI 1.48\u0026ndash;5.88) and ROP (OR 2.26, 95% CI 1.20\u0026ndash;4.25) was associated with increased odds of NDI or death when controlling for hyperoxia exposure and other baseline characteristics. Patients with severe BPD did not have increased odds of NDI (OR 1. 41, 95% CI 0.79\u0026ndash;2.52) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Gestational age, sex, and high MAP (\u0026gt;\u0026thinsp;10 cmH\u003csub\u003e2\u003c/sub\u003e0) were not significant independent risk factors for NDI or death (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). However, utilizing subgroup analysis for survivors only, severe IVH (OR 3.75, 95% CI 1.58\u0026ndash;9.16) and ROP (OR 2.63, 95% CI 1.32\u0026ndash;5.22) remained significant risk factors for NDI or death (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMultivariable Regression Model for Neurodevelopmental Impairment (NDI) Among Survivors\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRisk Factors/ Comorbidities\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo NDI\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;331)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNDI\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;100)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eHyperoxia Exposure\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo Hyperoxia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e156 (47.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (28.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003e--\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHyperoxia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e171 (52.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72 (72.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.39 (0.74\u0026ndash;2.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGestational Age (weeks)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41 (12.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (26.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u0026ndash;25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e102 (30.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e34 (34.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.86 (0.43\u0026ndash;1.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.68\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25\u0026ndash;26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e104 (31.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28 (28.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.60 (0.28\u0026ndash;1.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u0026ndash;27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e84 (25.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (12.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.48 (0.18\u0026ndash;1.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e170 (51.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37 (37.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e161 (48.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e63 (63.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.38 (0.91\u0026ndash;2.59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIntraventricular Hemorrhage (IVH)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot Severe (Grade 1\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e318 (96.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e84 (84.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere (Grade 3\u0026ndash;4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (3.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16 (16.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.75 (1.58\u0026ndash;9.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.003*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNecrotizing Enterocolitis (NEC)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo NEC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e312 (94.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e86 (86.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNEC Present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (5.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (14.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.77 (0.74\u0026ndash;4.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRetinopathy of Prematurity (ROP)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo ROP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e297 (91.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72 (73.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eROP Present\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (8.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (26.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.63 (1.32\u0026ndash;5.22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.006*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBronchopulmonary Dysplasia (BPD)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNone, Mild or Moderate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e136 (45.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (23.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e--\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSevere\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e161 (54.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e71 (76.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.28 (0.66\u0026ndash;2.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean Airway Pressure (MAP)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNone or Low (\u0026lt;\u0026thinsp;10 cm H\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e306 (92.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e83 (83.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedium or High (\u0026ge;\u0026thinsp;10 cm H\u003csub\u003e2\u003c/sub\u003eO)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (7.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (17.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.85 (0.84\u0026ndash;4.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Denotes statistical significance\u0026thinsp;\u0026le;\u0026thinsp;0.05. Reference group used for subgroup analysis indicated within table.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study aimed to investigate if prolonged hyperoxia exposure was independently associated with severe NDI or death. Our findings provide supporting evidence that infants requiring FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026ge;\u0026thinsp;0.4 for cumulative duration of at least three days have significantly increased odds of NDI or death. Optimal oxygen saturation (SpO\u003csub\u003e2\u003c/sub\u003e) in preterm infants is still under debate. Three large clinical studies including Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT), Benefits of Oxygen Saturation Targeting (BOOST) II and Canadian Oxygen Trial (COT) investigated lower versus higher SpO\u003csub\u003e2\u003c/sub\u003e target range in preterm infants less than 28 weeks\u0026rsquo; gestational age. The SUPPORT trial found that lower SpO\u003csub\u003e2\u003c/sub\u003e target range of 85\u0026ndash;89% increased risk of death before discharge compared to SpO\u003csub\u003e2\u003c/sub\u003e target range of 91\u0026ndash;95%, but overall mortality rates or NDI at 18 to 22 months\u0026rsquo; corrected age were no different(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e)\u003csup\u003e\u0026minus;\u003c/sup\u003e(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The BOOST II trial also demonstrated increased mortality rates in the lower SpO\u003csub\u003e2\u003c/sub\u003e group after changing their methodology for technical oximeter-calibration during their trial(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The COT trial found no difference in death or NDI at 18 months\u0026rsquo; corrected age (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). A Cochrane review that included late preterm infants found oxygen administration and oxygen target range did not have significant effect on mortality, but liberal oxygen administration had a significant increased risk for combined adverse outcome of death or retrolental fibroplasia(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) that included the above-mentioned studies, lower SpO2 target range of 85%-95% increased risk for death and NEC, but showed no difference in NDI(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA recent retrospective observational study of preterm neonates born less than 28 weeks\u0026rsquo; gestational age found that white matter injury of the brain was more prevalent in neonates with lower targeted SpO\u003csub\u003e2\u003c/sub\u003e (less than 90%) on magnetic resonance imaging (MRI), as well as in those with longer accumulated days requiring FiO\u003csub\u003e2\u003c/sub\u003e greater than 0.21. These factors were also associated with poorer neurodevelopmental assessment scores(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Supporting clinical studies, animal models have further demonstrated the detrimental impact of hyperoxia on brain injury, highlighting the potential mechanisms underlying neurological damage in premature neonates. During the infantile period, animals subjected to hyperoxia had brain injury due to various proposed mechanisms such as neuronal apoptosis, reduced brain mass, mitochondrial dysfunction, neurotrophin protection downregulation, reactive oxygen species (ROS) accumulation, inflammation-induced myelination disruption, as well as impairment of the axon-oligodendrocyte integrity and neuronal plasticity (\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). \u003cem\u003eIn vitro\u003c/em\u003e MRI imaging and histochemical analysis of brain tissue in mice exposed to FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026gt;\u0026thinsp;85% for 14 days revealed reduced hippocampal and cerebellar volume as well as associated impaired spatial and recognition memory (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Multiple animal studies have investigated the effects of prolonged hyperoxia on brain development, but there is a large variation in the animal model used as well as the degree of hyperoxia exposure (\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eClinical studies have predominantly focused on BPD as a risk factor for poor neurodevelopmental outcomes. However, to the authors\u0026rsquo; knowledge, none have examined prolonged cumulative exposure to FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026ge;\u0026thinsp;0.40 as an independent risk factor (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). There are several limitations to our study. First, this is a retrospective review and data on the corresponding SpO\u003csub\u003e2\u003c/sub\u003e at the time of FiO2 administration was unavailable which could limit the direct correlation between patient saturation and supplemental oxygen titration. We acknowledge the lack of concurrent SpO\u003csub\u003e2\u003c/sub\u003e data may cause difficulties in identifying critically ill patients that may need higher supplemental oxygen support. Our neonatal intensive care unit follows a protocol to keep SpO\u003csub\u003e2\u003c/sub\u003e target range between 90\u0026ndash;95% for premature infants. Additionally, SpO\u003csub\u003e2\u003c/sub\u003e values alone do not capture the severity of lung disease. To address this limitation, MAP values were incorporated to account for the degree of lung severity and overall clinical illness. Another limitation is FiO\u003csub\u003e2\u003c/sub\u003e levels is not a direct measure of O\u003csub\u003e2\u003c/sub\u003e delivery to tissues. Although measured arterial oxygen levels would provide a more accurate assessment of whether FiO\u003csub\u003e2\u003c/sub\u003e administration was excessive, the limited availability of arterial blood gas values constrained their use in this study. Lastly, in our patient population, there was a high mortality rate in the hyperoxia group. This introduces a potential bias, as death itself may have a more significant impact on outcomes than hyperoxia, potentially confounding the interpretation of the relationship between hyperoxia and clinical outcomes. Lastly, many infant deaths occurred in the hyperoxia group, and separating the mortality group from the hyperoxia group would have significantly reduced our sample size. As a result, both groups were included in our primary analysis.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, oxygen is a critical therapy in the management of extremely premature infants born under 28 weeks\u0026rsquo; gestational age, but prolonged and excessive exposure to oxygen may be a significant and independent risk factor for development of long-term moderate to severe NDI including death. Our study adds to current literature by focusing on the administration of supplemental oxygen via positive pressure ventilation in preterm neonates and its association with death and adverse neurodevelopmental outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflict of Interest:\u003c/h2\u003e\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\u003ch2\u003eEthics Statement:\u003c/h2\u003e\u003cp\u003e Data retrieval and review were approved by McGovern Medical School at the University of Texas Health Science Center at Houston IRB review board (HSC-MS21-0335). Consent waived as this is a retrospective review.\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eTF is supported by KL2 TR003168, UL1 TR003167. WL is partly supported by UL1TR003167. TT is supported by T32 5T32GM135118\u003c/p\u003e\u003ch2\u003eAuthor Contributions:\u003c/h2\u003e\u003cp\u003eTTT and TF responsible for conceptualization and revision of paper. NS, LI, TL, SM and AJ carried out data acquisition. TTT, WL, AFC, AK and TF analyzed and interpreted data.\u003c/p\u003e\u003ch2\u003eData Availability Statement:\u003c/h2\u003e\u003cp\u003eData published in article can be made available via request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSardesai S, Biniwale M, Wertheimer F, Garingo A, Ramanathan R. Evolution of surfactant therapy for respiratory distress syndrome: past, present, and future. Pediatr Res. 2017;81(1\u0026ndash;2):240\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNkadi PO, Merritt TA, Pillers DA. An overview of pulmonary surfactant in the neonate: genetics, metabolism, and the role of surfactant in health and disease. Mol Genet Metab. 2009;97(2):95\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCannav\u0026ograve; L, Perrone S, Viola V, Marseglia L, Di Rosa G, Gitto E. Oxidative Stress and Respiratory Diseases in Preterm Newborns. Int J Mol Sci. 2021;22(22).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAuten RL, Davis JM. Oxygen Toxicity and Reactive Oxygen Species: The Devil Is in the Details. Pediatric Research. 2009;66(2):121\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGiusto K, Wanczyk H, Jensen T, Finck C. Hyperoxia-induced bronchopulmonary dysplasia: better models for better therapies. Dis Model Mech. 2021;14(2).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbiramalatha T, Ramaswamy VV, Bandyopadhyay T, Somanath SH, Shaik NB, Pullattayil AK, et al. Interventions to Prevent Bronchopulmonary Dysplasia in Preterm Neonates: An Umbrella Review of Systematic Reviews and Meta-analyses. JAMA Pediatr. 2022;176(5):502\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGilfillan M, Bhandari A, Bhandari V. Diagnosis and management of bronchopulmonary dysplasia. Bmj. 2021;375:n1974.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBerger J, Bhandari V. Animal models of bronchopulmonary dysplasia. The term mouse models. Am J Physiol Lung Cell Mol Physiol. 2014;307(12):L936-47.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBuczynski BW, Maduekwe ET, O'Reilly MA. The role of hyperoxia in the pathogenesis of experimental BPD. Semin Perinatol. 2013;37(2):69\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYounge N, Goldstein RF, Bann CM, Hintz SR, Patel RM, Smith PB, et al. Survival and Neurodevelopmental Outcomes among Periviable Infants. N Engl J Med. 2017;376(7):617\u0026ndash;28.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJohnson S, Moore T, Marlow N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? Pediatr Res. 2014;75(5):670\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJensen EA, Dysart K, Gantz MG, McDonald S, Bamat NA, Keszler M, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBamat N, Fierro J, Wang Y, Millar D, Kirpalani H. Positive end-expiratory pressure for preterm infants requiring conventional mechanical ventilation for respiratory distress syndrome or bronchopulmonary dysplasia. Cochrane Database of Systematic Reviews. 2019(2).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChioma R, Healy DB, Finn D, Walsh BH, Reynolds C, O'Sullivan D, et al. The Bronchopulmonary Dysplasia score: A predictive model for bronchopulmonary dysplasia or death in high-risk preterm infants. Acta Paediatrica. 2024;113(8):1781\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNetwork SSGotEKSNNR, Carlo WA, Finer NN, Walsh MC, Rich W, Gantz MG, et al. Target ranges of oxygen saturation in extremely preterm infants. The New England journal of medicine. 2010;362(21):1959\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVaucher YE, Peralta-Carcelen M, Finer NN, Carlo WA, Gantz MG, Walsh MC, et al. Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med. 2012;367(26):2495\u0026ndash;504.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRamani M, van Groen T, Kadish I, Bulger A, Ambalavanan N. Neurodevelopmental impairment following neonatal hyperoxia in the mouse. Neurobiol Dis. 2013;50:69\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchmidt B, Whyte RK, Asztalos EV, Moddemann D, Poets C, Rabi Y, et al. Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: a randomized clinical trial. Jama. 2013;309(20):2111\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAskie LM, Henderson-Smart DJ, Ko H. Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants. Cochrane Database Syst Rev. 2009;2009(1):Cd001077.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAskie LM, Darlow BA, Finer N, Schmidt B, Stenson B, Tarnow-Mordi W, et al. Association Between Oxygen Saturation Targeting and Death or Disability in Extremely Preterm Infants in the Neonatal Oxygenation Prospective Meta-analysis Collaboration. Jama. 2018;319(21):2190\u0026ndash;201.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRantakari K, Rinta-Koski O-P, Mets\u0026auml;ranta M, Hollm\u0026eacute;n J, S\u0026auml;rkk\u0026auml; S, Rahkonen P, et al. Early oxygen levels contribute to brain injury in extremely preterm infants. Pediatric Research. 2021;90(1):131\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFelderhoff-Mueser U, Bittigau P, Sifringer M, Jarosz B, Korobowicz E, Mahler L, et al. Oxygen causes cell death in the developing brain. Neurobiology of Disease. 2004;17(2):273\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIkonomidou C, Kaindl AM. Neuronal death and oxidative stress in the developing brain. Antioxid Redox Signal. 2011;14(8):1535\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMilton VJ, Sweeney ST. Oxidative stress in synapse development and function. Dev Neurobiol. 2012;72(1):100\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePrager S, Singer BB, Bendix I, Schlager GW, Bertling F, Ceylan B, et al. 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Caspase-1 Inhibition Attenuates Hyperoxia-induced Lung and Brain Injury in Neonatal Mice. Am J Respir Cell Mol Biol. 2019;61(3):341\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHoehn T, Felderhoff-Mueser U, Maschewski K, Stadelmann C, Sifringer M, Bittigau P, et al. Hyperoxia Causes Inducible Nitric Oxide Synthase-Mediated Cellular Damage to the Immature Rat Brain. Pediatric Research. 2003;54(2):179\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchmidt B, Asztalos EV, Roberts RS, Robertson CMT, Sauve RS, Whitfield MF, et al. Impact of Bronchopulmonary Dysplasia, Brain Injury, and Severe Retinopathy on the Outcome of Extremely Low-Birth-Weight Infants at 18 Months: Results From the Trial of Indomethacin Prophylaxis in Preterms. JAMA. 2003;289(9):1124\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMalavolti AM, Bassler D, Arlettaz-Mieth R, Faldella G, Latal B, Natalucci G. Bronchopulmonary dysplasia-impact of severity and timing of diagnosis on neurodevelopment of preterm infants: a retrospective cohort study. BMJ paediatrics open. 2018;2(1):e000165-e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIsayama T, Lee SK, Yang J, Lee D, Daspal S, Dunn M, et al. Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. JAMA Pediatrics. 2017;171(3):271\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hyperoxia, neurodevelopmental impairment, extremely premature neonates","lastPublishedDoi":"10.21203/rs.3.rs-7428681/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7428681/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRetrospective cohort study of extremely preterm infants (\u0026lt;\u0026thinsp;28 weeks\u0026rsquo; gestational age and birth weight\u0026thinsp;\u0026le;\u0026thinsp;1500 g) treated at a level IV academic hospital from January 2008 to July 2018 to assess if prolonged hyperoxia is an independent risk factor for severe neurodevelopmental impairment (NDI) or death.\u003c/p\u003e\u003cp\u003eAmong 546 former extremely preterm infants, 327 (59.9%) were exposed to prolonged hyperoxia. Prolonged hyperoxia was associated with increased odds of severe NDI or death (OR 1.77, 95% CI 1.01 to 3.14) after adjusting for risk factors. When the components of the primary outcome were analyzed separately, prolonged hyperoxia was not associated with severe NDI among survivors (OR 1.39, 95% CI 0.74 to 2.63) but was associated with death (OR 3.20, 95% CI 1.23 to 9.59). In conclusion, prolonged exposure to oxygen is a significant and independent risk factor for development of long-term moderate to severe NDI including death.\u003c/p\u003e","manuscriptTitle":"Prolonged Hyperoxia Exposure is an Independent Predictor for Moderate to Severe Neurodevelopmental Impairment in Extremely Premature Neonates","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 10:26:05","doi":"10.21203/rs.3.rs-7428681/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7cafd09e-a9ec-4cfa-a27e-10a1ccbae8be","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53611223,"name":"Health sciences/Risk factors"},{"id":53611224,"name":"Health sciences/Diseases/Neurological disorders/Neurodevelopmental disorders"}],"tags":[],"updatedAt":"2025-09-22T14:30:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 10:26:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7428681","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7428681","identity":"rs-7428681","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}