Association of Low Hospital Birth Volume and Adverse Short-Term Outcomes for Neonates Treated with Therapeutic Hypothermia in Rural States

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Study Design: Multicenter retrospective study comparing outcomes for small (1500 births/year) hospitals in Northern New England. Multivariable logistic regression assessed the combined outcome of death/severe gray matter injury on MRI, controlling for encephalopathy severity and time to initiation of TH. Results: 531 neonates were included from small (N=120), medium (N=193), and large (N=218) volume hospitals and TH was initiated at a median of 4.5, 4, and 2 hours of life respectively. The odds of the combined outcome were 4.3-fold higher in small versus large birth volume hospitals (95% CI = 1.6, 12.1, p=0.004), but not different in medium birth volume hospitals. Conclusion: Neonates born in small volume hospitals had significantly higher odds of death or severe gray matter injury following TH. Health sciences/Diseases/Neurological disorders/Brain injuries Health sciences/Risk factors Figures Figure 1 Introduction Timely identification and treatment of neonates who meet criteria for therapeutic hypothermia (TH) poses significant challenges in rural settings, where access to intensive care, neonatal specialists, and diagnostic resources may be limited. The literature is variable regarding whether outborn neonates treated with TH have more frequent adverse outcomes compared to inborn neonates. Assessing this association is challenging due various factors that are linked with being born in a non-tertiary care setting. Outborn neonates are often not resuscitated by clinicians with the same skill set and experience as neonatologists, suggesting that resuscitation practices may play a role. Outborn neonates also must be transferred from the birth hospital to the NICU, which can delay initiation of TH and make early temperature management during transport challenging(1-3). Time to reach target temperature for effective therapy can also vary and occur beyond the six-hour goal(4). Lastly, there may be differences in the overall health and pregnancy care of the mothers delivering in one setting versus the other. Many studies have commented on the presence or absence of differences in outcomes for neonates born outside a hypothermia center, even if the study was not expressly designed to assess this question. Findings have ranged from studies that report that the majority of deaths occur in outborns(5), to a re-analysis of clinical trial data showing no difference in the benefit of therapeutic hypothermia for those who were inborn versus outborn(6, 7). However, other evidence suggests worse outcomes among outborn encephalopathic neonates with lower rates of seizure free survival(8, 9). Sabsabi et. al concluded that the level of care of the birth hospital in a metropolitan region of Canada significantly impacts outcomes, with neonates born at level one centers experiencing worse outcomes compared to neonates born at level two or three medical centers(10). Given these conflicting findings, we sought to evaluate our data from four Northern New England tertiary care centers, aiming to reconsider outborn neonates not as a single homogeneous group, but rather as a population with varying levels of risk for adverse outcomes based on the annual birth volume of their hospital of origin. We hypothesized that the risk of short-term adverse outcomes would be higher for outborn neonates transported from small (up to 500 births per year) and medium birth volume hospitals (501-1500 births per year), compared to those born in large volume hospitals (more than 1500 births per year), where TH is performed on-site. The goal of this investigation was to achieve a more nuanced understanding of the risks associated with being born in a rural setting and outcome after TH. Methods Study Design : A retrospective cohort study of neonates treated with TH at four tertiary care centers that participate in the Northeast Regional Hypothermia Consortium (see Supplement 1 for details about each institution). Primary Outcome: The primary outcome was in-hospital mortality or severe gray matter injury on brain MRI. Severe gray matter injury was defined by gray matter sub-score ≥9.5 per the Weeke scoring system, found to be 92% sensitive and 95% specific for an abnormal developmental outcome at 2 years defined as death, cerebral palsy (Gross Motor Function Classification System ≥ II), or Bayley Scales of Infant and Toddler Development with scores <85(11). The gray matter injury score was assigned by a team including a neuroradiologist and a pediatric neurologist who reviewed images from all sites. Classification of hospitals: Hospitals were grouped according to annual birth volume. Small hospitals were defined as a birth rate of 1-500 neonates per year, medium hospitals were defined as a birth rate of 501-1500 neonates per year, and large hospitals (tertiary care centers) all had more than 1500 births per year and were also the centers where TH was implemented. Environment: At all four tertiary care centers, TH is employed for neonates who are less than six hours old at the time of initiation, are greater than or equal to 35 weeks gestation, and who have evidence of perinatal asphyxia with moderate or severe encephalopathy categorized by exam during the first six-hours of life. All four institutions maintain the 33-34°C temperature for 72 hours and rewarm over 12 hours with continuous EEG monitoring. Study Inclusion/Exclusion Criteria: Neonates were included if they were treated with TH for HIE at any of the four centers. We excluded neonates who were less than 35 weeks' gestation, completed less than 72 hours of TH, did not undergo brain MRI per family preference, or were transferred to a different institution due to the potential need for extracorporeal membrane oxygenation (ECMO) prior to obtaining a brain MRI. Neonates who were delivered at home or in small birthing centers were also excluded (Figure 1). Database: Data were manually extracted from the electronic medical record by trained research coordinators at each of the tertiary care centers. This study was approved by the institutional review board at each tertiary care center as exempt research. Statistical Analysis: Statistical analysis was conducted using R v.4.2.1. Baseline differences between neonates grouped according to birth volume of hospital in which they were born (small, medium and large) were compared using chi square tests or Fisher’s Exact Tests for categorical variables and t-tests or Kruskal-Wallis rank sum tests for continuous variables. A composite outcome of in-hospital mortality and gray matter injury score ≥9.5 was created to reflect severe outcomes that differ primarily by parental decision making(12, 13). Logistic mixed effects regression analysis was performed to investigate the effect of birth hospital size on the odds of the composite outcome while controlling for possible confounders. Confounders were identified by having a statistical association with both birth volume of the hospital and the composite outcome. Covariates with just an association with the outcome (cutoff of p < 0.2), as well as study site were also included in the full model to improve the precision of estimates. Stepwise selection was performed on the full model using the stepAIC function from the MASS package in R to achieve the most parsimonious model. A mediation analysis with 1,000 bootstrapped samples was also performed using the mediation package in R to assess the contribution of time to initiation of TH on the difference between outcomes for small versus large birth volume hospitals and medium versus large birth volume hospitals. Results From 2010-2024, a total of 531 neonates were treated with TH across the four participating centers after 38 were excluded (Figure 1). Two hundred and eighteen neonates (41%) were inborn and 313 (59%) neonates were outborn. There were 120 outborn from small birth volume hospitals and 193 from medium birth volume hospitals. Mothers in small and medium birth volume hospitals were younger and had fewer medical comorbidities (Table 1). Tobacco use was highest for mothers in small birth volume hospitals, and mothers from both small and medium birth volume hospitals had higher rates of marijuana use. There were no significant differences in the rate of Cesarean section or delivery related complications, including placental abruption, cord prolapse, shoulder dystocia, or late fetal heart rate decelerations, however chorioamnionitis and uterine rupture occurred significantly more frequently in the large birth volume hospitals. Neonates in large birth volume hospitals skewed to a younger gestational age (Table 2). The umbilical cord gases demonstrated a greater degree of acidemia for neonates born in medium and large volume hospitals. There were significantly fewer cord gases collected in both small and medium birth volume hospitals. Small birth volume hospitals had the greatest proportions of neonates with mild and severe encephalopathy (Table 2). The frequency of seizures and severe brain injury on MRI was not statistically significantly different by hospital birth volume (Table 3). Mortality prior to hospital discharge was highest among neonates born at small birth volume hospitals (12%) compared to 3.6% and 6% for medium and high birth volume hospitals, respectively (p=0.008). The composite adverse outcome of in-hospital mortality or severe gray matter injury on MRI occurred for significantly more neonates from small birth volume hospitals (16%) compared to 6% from medium volume and 7% from large volume hospitals (p=0.002). Time to initiation of TH was significantly delayed for both small and medium hospitals, a median of 4.5 and 4 hours, respectively, compared to a median of 2 hours for large volume hospitals (p<0.001). The full regression model included severity of encephalopathy, time to initiation of TH and the interaction between these two, as well as center where hypothermia was performed, plus additional variables that differed between neonates with and without the primary outcome of death or severe grey matter injury (cesarean section, prolapsed cord, and shoulder dystocia). After stepwise selection, the final model included birth volume and encephalopathy severity. The odds of gray matter injury or death was 4.3 times higher in low birth volume compared to high birth volume hospitals (95% CI = 1.6, 12.1, p=0.004). There was no difference in odds of gray matter injury or death between medium and high birth volume hospitals (p = 0.498). Time to initiation of TH did not mediate the association between small versus large birth volume hospital and the composite outcome (p=0.946). Discussion In this analysis of neonates treated with TH in rural Northern New England, we assessed outcomes for outborns according to the annual birth volume of their hospital of origin. We found that neonates born in small birth volume hospitals compared to large birth volume hospitals have significantly higher odds of death or severe grey matter injury on brain MRI and that the delayed initiation of TH did not contribute to this difference in outcome. Contrary to our hypothesis, the odds of death or severe gray matter injury on brain MRI were not higher for neonates born in medium birth volume hospitals compared to large birth volume hospitals. Our analysis is the second to consider outborn neonates as subgroups rather than as a homogeneous entity. This type of analysis was first performed by Sabsabi et al who investigated the impact of birthplace (birth in Level I, II or III nursery) on outcome for asphyxiated neonates(10). They found a higher incidence of asphyxia for neonates born in lower care level settings (e.g. level 1 birth centers) compared to Level III centers. In multivariate analysis, birth in a level 1 birth center was associated with a 2-fold higher risk of either death or brain injury. Our results were similar, although the magnitude was higher with 4-fold increased odds of death or brain injury on MRI. One possible reason for the difference in magnitude could be that our population is primarily rural, whereas the Sabsabi study was done in an urban environment(14-16). Another possible reason could relate to the fact that the Sabsabi study was done in a country with nationalized healthcare, a system that has a known association with better outcomes(17). Small birth volume hospitals are intrinsically different from medium and large birth volume hospitals for several reasons. First, for small birth volume hospitals, the ability to perform an emergency Cesarean section within the standard 30-minute window may not be feasible(18). Small birth volume hospitals are also less likely to have in-house pediatrician coverage to attend deliveries. This may leave the immediate resuscitation of an asphyxiated neonate in the hands of labor and delivery staff members who may have less experience in neonatal resuscitation(19, 20). This is not the case for medium and large birth volume hospitals, which usually have around the clock coverage provided by pediatricians, pediatric hospitalists, or neonatal nurse practitioners who are more experienced in neonatal resuscitation. In a propensity score-matched analysis of neonates born in the United Kingdom, Shipley et al reported that delivery at hospitals with TH capability was associated with a greater proportion of seizure-free survival (35%), compared to delivery at centers without the ability to provide TH (31% seizure-free survival)(8). Unlike our study, the Shipley et. al. study did not appreciate a significant difference in mortality according to location of birth. This may be attributable to the fact that in the UK, TH can be performed in Level 2 and 3 centers and in this study only 14% of the study population came from Level 1 hospitals, whereas in our study nearly one-quarter of our patients are from Level-1 hospitals. In another large retrospective propensity matched analysis from the Pediatrix group, the authors also did not find a statistically significant higher rate of mortality for outborn neonates(9). However, surviving outborn neonates had significantly higher rates of seizures and gastrostomy tube placement suggesting a difference in morbidity associated with perinatal hypoxia-ischemia. The outcome measures used in these large studies were chosen as available short-term outcomes since longer term outcome measures such as formal neurodevelopmental assessments such as the Bayley Scales of Infant Development (BSID) were not available. Unfortunately, our study also did not have long term data results to analyze neurodevelopmental outcomes after hospital discharge. Time to initiation of therapeutic hypothermia has been linked to the question of outcome differences for inborn versus outborn neonates. Neonates born outside of a TH center typically have later initiation of TH, which we observed in both small and medium birth volume hospitals in this study. The relationship of earlier time to initiation of TH with improved outcome was first highlighted in preclinical experiments(21-23). In an observational study in humans, Thoresen et. al. demonstrated that surviving neonates with initiation of TH before three hours of life had better motor outcomes at 18-20 months compared to those with initiation after three hours(24). These data, combined with the knowledge that initiation of TH after 6 hours of life had a low probability of benefit(25) resulted in a sense of urgency to initiate TH as quickly as possible. More recent work has re-assessed this urgency. A retrospective cohort of 91 Canadian born neonates assessed outcome by early (median of 1.4 hours) versus late initiation (median of 4.4 hours) of TH, no differences in the severity of brain injury on MRI or in neurodevelopmental outcomes at 18 months were appreciated(26). A recent secondary analysis of the 500 neonates enrolled in the HEAL Study(27) also did not demonstrate differences in short-term outcomes or 2-year neurodevelopmental outcomes for early (4 hours) attainment of the target temperature(28). Time to initiation is confounded by the fact that neonates with severe encephalopathy tend to have TH initiated the soonest, but also have the highest rate of adverse outcome, which was why we chose to use severity of encephalopathy by time to initiation as an interaction term in our regression analysis. Additionally, the timing of the hypoxic ischemic injury onset is often not known with certainty. Our results echo these other clinical studies(26, 28) indicating that time to initiation does not affect outcome. Our study has several strengths, including a unique consortium, formed by investigators from four NICUs in three of the most rural states in the United States: Maine, New Hampshire and Vermont. This novel consortium has allowed us to collect and analyze data that is not routinely available outside of major academic children's hospitals. With the combination of four NICU’s, our sample size is large for data sets emerging out of rural areas and may be generalizable to other more rural locations. We used advanced statistical analyses to assess the relationship between outcome and hospital size taking into consideration both severity of encephalopathy and time to initiation of TH, as well as other potential confounders such as site. Additionally, we collected the degree of encephalopathy for all neonates in the study, and our combined outcome captures both mortality and the severe impairment expected in children with high gray matter injury scores on MRI. This combined outcome is key in our opinion as the consequence of either death or severe gray matter injury is most often the result of parental decision making rather than the inability of a neonate to survive(29). Another strength is that we chose to exclude those born in birthing centers and home births which confer a higher risk for adverse outcome(30). There are several weaknesses in this study, which include the lack of comprehensive data on longer term neurodevelopmental outcomes, and no data on time from birth to target temperature. Additionally, some data on outborn neonates was missing. For example, there were many more missing cord gases for neonates born in both small and medium birth volume hospitals, a challenge reported by others studying TH and outcomes in outborn neonates(3). There is also likely to be some residual confounding from sociodemographic variable differences for deliveries that occur in small and medium birth volume hospitals (e.g. incomplete data on drug exposure, socioeconomic status and prenatal care). This may have resulted in an overestimate of the difference in odds of adverse outcome between small and large birth volume hospitals. Finally, although each institution follows a standardized hypothermia protocol that has strong similarities between institutions, there are likely nuanced differences between institutions that are not captured by the data. We attempted to address this by controlling for site in the stepwise regression model. An additional limitation is the potential for changes in practice across time from 2010-2024. Use of a structured neonatal encephalopathy exam came into more widespread use during the epoch studied and it is very possible that intra-site differences in quality and conclusions of the exam changed during that time, particularly in differentiating mild from moderate encephalopathy. Conclusions This analysis evaluated neonates treated with therapeutic hypothermia from three rural states and separated the neonates that were treated with TH into subgroups based on the birth volume of the hospital of origin. We found that births in small compared to large birth volume hospitals have significantly higher odds of death or severe gray matter injury on MRI. This was not the case for medium volume hospitals, and our results did not show an effect of time to initiate TH on outcome. Further analysis is needed to delineate the obstetric and neonatal resuscitation factors that may be involved in our finding of increased morbidity and mortality associated with lower birth volume hospitals in these three rural states. Potential strategies to support neonatal resuscitation and stabilization may be needed in these small, often critical access rural community hospitals. The use of telehealth modalities may facilitate interactions between expert subspecialists and primary care providers in these efforts to improve outcomes. Abbreviations EEG Electroencephalogram HIE Hypoxic Ischemic Encephalopathy MMC Maine Medical Center MRI Magnetic resonance imaging NE Neonatal Encephalopathy NICU Neonatal Intensive Care Unit NLEMMC Northern Light Eastern Maine Medical Center TH Therapeutic hypothermia UVMMC University of Vermont Medical Center Declarations Funding Sources: Dr. Craig, Ms. Cutler and Ms. Seften were supported by grant 1P20GM139745-01 from the National Institutes of Health for the Center of Biomedical Research Excellence in Acute Care Research and Rural Disparities. Dr. Craig and the REDCap administrator were also supported by U54 GM115516 from the Northern New England Clinical and Translational Research network which funds the MaineHealth instance of REDCap. Conflict of Interest Disclosure : The authors have no conflicts of interest to disclose. Acknowledgements: The authors thank the individuals who contributed to data collection; Megan Berube, MD, Leah Fox, MD, Lauren McAllister, MD, and Sophi Aronson from MMC as well as Emily Fraser-Read. Delaney Davis, and Krysta Anderson from NLEMMC and Jessica Moya from Elliot Hospital. Melanie Parziale, MD from The University of Vermont, Larner College of Medicine. References Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010;30(5):324-9. O'Reilly D, Labrecque M, O'Melia M, Bacic J, Hansen A, Soul JS. Passive cooling during transport of asphyxiated term newborns. J Perinatol. 2013;33(6):435-40. Harbert MJA, Sey R, Arnell K, Rasmussen M. Identifying Ways to Fix Outcome Disparities among Outborns Needing Therapeutic Hypothermia. Am J Perinatol. 2021;38(S 01):e21-e5. Simbruner G, Mittal RA, Rohlmann F, Muche R, neo.n EnTP. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010;126(4):e771-8. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005;32(1):11-7. Natarajan G, Pappas A, Shankaran S, Laptook AR, Walsh M, McDonald SA, et al. Effect of inborn vs. outborn delivery on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy: secondary analyses of the NICHD whole-body cooling trial. Pediatr Res. 2012;72(4):414-9. Thayyil S, Montaldo P, Krishnan V, Ivain P, Pant S, Lally PJ, et al. Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities: A Nested Study Within a Randomized Clinical Trial. JAMA Netw Open. 2023;6(5):e2312152. Shipley L, Mistry A, Sharkey D. Outcomes of neonatal hypoxic-ischaemic encephalopathy in centres with and without active therapeutic hypothermia: a nationwide propensity score-matched analysis. Arch Dis Child Fetal Neonatal Ed. 2022;107(1):6-12. Stetson RC, Brumbaugh JE, Weaver AL, Mara KC, Clark RH, Carey WA, et al. Association of outborn versus inborn birth status on the in-hospital outcomes of neonates treated with therapeutic hypothermia: A propensity score-weighted cohort study. Resuscitation. 2021;167:82-8. Sabsabi B, Huet C, Rampakakis E, Beltempo M, Brown R, Lodygensky GA, et al. Asphyxiated Neonates Treated with Hypothermia: Birth Place Matters. Am J Perinatol. 2022;39(3):298-306. Weeke LC, Groenendaal F, Mudigonda K, Blennow M, Lequin MH, Meiners LC, et al. A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia. J Pediatr. 2018;192:33-40 e2. Natarajan G, Mathur A, Zaniletti I, DiGeronimo R, Lee KS, Rao R, et al. Withdrawal of Life-Support in Neonatal Hypoxic-Ischemic Encephalopathy. Pediatr Neurol. 2019;91:20-6. Wilkinson D. MRI and withdrawal of life support from newborn infants with hypoxic-ischemic encephalopathy. Pediatrics. 2010;126(2):e451-8. Lisonkova S, Haslam MD, Dahlgren L, Chen I, Synnes AR, Lim KI. Maternal morbidity and perinatal outcomes among women in rural versus urban areas. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2016;188(17-18):E456-E65. Ely DM, Hoyert DL. Differences Between Rural and Urban Areas in Mortality Rates for the Leading Causes of Infant Death: United States, 2013-2015. NCHS Data Brief. 2018(300):1-8. Ehrenthal DB, Kuo HD, Kirby RS. Infant Mortality in Rural and Nonrural Counties in the United States. Pediatrics. 2020;146(5). Weaver MR, Nandakumar V, Joffe J, Barber RM, Fullman N, Singh A, et al. Variation in Health Care Access and Quality Among US States and High-Income Countries With Universal Health Insurance Coverage. JAMA Netw Open. 2021;4(6):e2114730. Mooney SE, Ogrinc G, Steadman W. Improving emergency caesarean delivery response times at a rural community hospital. Quality & safety in health care. 2007;16(1):60-6. Jukkala AM, Henly SJ. Provider readiness for neonatal resuscitation in rural hospitals. J Obstet Gynecol Neonatal Nurs. 2009;38(4):443-52. Zanno A, Melendi M, Cutler A, Stone B, Chipman M, Holmes J, et al. Simulation-Based Outreach Program Improves Rural Hospitals' Team Confidence in Neonatal Resuscitation. Cureus. 2022;14(9):e28670. Gunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res. 1999;46(3):274-80. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997;99(2):248-56. Iwata O, Iwata S, Tamura M, Nakamura T, Sugiura M, Ogiso Y, et al. Early head cooling in newborn piglets is neuroprotective even in the absence of profound systemic hypothermia. Pediatrics international : official journal of the Japan Pediatric Society. 2003;45(5):522-9. Thoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology. 2013;104(3):228-33. Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, et al. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017;318(16):1550-60. Guillot M, Philippe M, Miller E, Davila J, Barrowman NJ, Harrison MA, et al. 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Tables Table 1: Characteristics of Birth Parent and Delivery by Hospital Birth Volume Characteristic 0-500 , N = 120 1 501-1500 , N = 193 1 1501+ , N = 218 1 p-value 2 Maternal Age 29.0 (23.0, 32.2) 30.0 (24.0, 33.0) 31.0 (26.0, 34.0) 0.016 Gestational Diabetes 11 (9.2%) 20 (10%) 28 (13%) 0.6 Preeclampsia/Eclampsia 11 (9.2%) 12 (6.2%) 29 (13%) 0.053 Multiple Gestation 1 (0.8%) 1 (0.5%) 12 (5.5%) 0.003 Tobacco 20 (17%) 16 (8.3%) 17 (7.8%) 0.021 Opioids 11 (9.2%) 10 (5.2%) 16 (7.3%) 0.4 SSRIs 9 (7.5%) 26 (13%) 24 (11%) 0.3 Benzodiazepines 1 (0.8%) 4 (2.1%) 2 (0.9%) 0.6 Marijuana 20 (17%) 27 (14%) 15 (6.8%) 0.013 Maternal fever 9 (7.5%) 8 (4.1%) 14 (6.4%) 0.4 GBS positive 29 (24%) 32 (17%) 56 (26%) 0.083 Chorioamnionitis 5 (4.2%) 7 (3.6%) 32 (15%) <0.001 Prolonged Rupture of Membranes 18 (15%) 24 (12%) 29 (13%) 0.8 Late Decelerations 17 (14%) 33 (17%) 26 (12%) 0.3 C-Section 63 (52%) 98 (51%) 120 (55%) 0.7 Shoulder Dystocia 11 (9.2%) 19 (9.8%) 27 (12%) 0.6 Prolapsed Cord 3 (2.5%) 7 (3.6%) 6 (2.7%) 0.9 Placental Abruption 9 (7.5%) 24 (12%) 18 (8.2%) 0.2 Uterine Rupture 0 (0%) 4 (2.1%) 10 (4.6%) 0.03 1 Median (IQR); n (%) 2 Kruskal-Wallis rank sum test; Pearson's Chi-squared test; Fisher's exact test Table 2: Characteristics of Newborns by Hospital Birth Volume Characteristic 0-500 , N = 120 1 501-1500 , N = 193 1 1501+ , N = 218 1 p-value 2 Gestational Age 39.00 (38.00, 40.00) 39.00 (38.00, 40.00) 39.00 (37.00, 40.00) 0.002 Gestational Age <37 wks 13 (11%) 18 (9.3%) 33 (15%) 0.2 Birth Weight (kg) 3.40 (3.00, 3.75) 3.35 (2.96, 3.73) 3.27 (2.89, 3.67) 0.2 Male Sex 65 (54%) 109 (56%) 125 (57%) 0.9 APGAR 1 min 2 (1, 3) 2 (1, 3) 2 (1, 3) 0.2 Not documented 1 0 0 APGAR 5 min 4. (3, 5) 5 (3, 7) 5 (3, 6) <0.001 Not documented 1 0 0 APGAR 10 min 6 (4, 7) 6 (5, 8) 6 (5, 7) 0.008 Not documented 15 22 36 Arterial Cord pH 7.15 (7.02, 7.27) 7.08 (6.96, 7.20) 7.07 (6.94, 7.20) 0.005 Not collected 59 58 39 Venous Cord pH 7.23 (7.07, 7.28) 7.19 (7.07, 7.29) 7.22 (7.08, 7.29) >0.9 Not collected 70 64 36 Severity of HIE 0.009 Mild 27 (22%) 34 (18%) 24 (11%) Moderate 76(63%) 146 (76%) 169 (78%) Severe 17 (14%) 13 (6.7%) 25 (11%) 1 Median (IQR); n (%) 2 Kruskal-Wallis rank sum test; Pearson's Chi-squared test; Fisher's exact test Table 3: Short-term Outcomes of Newborns by Hospital Birth Volume Characteristic 0-500 , N = 120 1 501-1500 , N = 193 1 1501+ , N = 218 1 p-value 2 Death 15 (12%) 7 (3.6%) 13 (6.0%) 0.008 Severe grey matter injury 8 (8%) 7 (6%) 8 (7%) 0.7 Death or severe grey matter injury 19 (16%) 11 (6%) 15 (7%) 0.004 Seizure 30 (25%) 53 (27%) 46 (21%) 0.3 Time to TH Initiation in hours (IQR) 4.50 (3.00, 5.67) 4.00 (3.00, 5.00) 2.00 (1.00, 3.50) <0.001 1 Median (IQR); n (%) 2 Kruskal-Wallis rank sum test; Pearson's Chi-squared test; Fisher's exact test Additional Declarations There is NO conflict of interest to disclose. Supplementary Files SupplementalTable111.5.24.docx Cite Share Download PDF Status: Published Journal Publication published 06 Jul, 2025 Read the published version in Journal of Perinatology → Version 1 posted Editorial decision: revise 10 Jan, 2025 Review # 1 received at journal 20 Nov, 2024 Reviewer # 1 agreed at journal 15 Nov, 2024 Reviewers invited by journal 15 Nov, 2024 Submission checks completed at journal 12 Nov, 2024 First submitted to journal 11 Nov, 2024 Unknown event 07 Nov, 2024 Editor assigned by journal 06 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5404622","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":378619863,"identity":"e059f58e-640a-42c1-9884-1cc03e7a9151","order_by":0,"name":"Alexa Craig","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-6477-3390","institution":"Barbara Bush Children's Hospital at Maine Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Alexa","middleName":"","lastName":"Craig","suffix":""},{"id":378619864,"identity":"ce29482b-e673-4776-9ccc-276ef97ed548","order_by":1,"name":"Anya Cutler","email":"","orcid":"https://orcid.org/0000-0003-3439-9606","institution":"MaineHealth Institute for 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15:48:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":76009,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5404622/v1/246db8b9e397555abc2b490c.png"},{"id":86090342,"identity":"cffdf07f-d64d-4e73-930f-3b08cf65363d","added_by":"auto","created_at":"2025-07-06 07:05:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":960089,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5404622/v1/93b01951-aa5b-47d8-be7c-e2a2949899a3.pdf"},{"id":71793914,"identity":"279c3b4b-539a-4a51-9a3d-b696164ac732","added_by":"auto","created_at":"2024-12-18 15:48:39","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13842,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementalTable111.5.24.docx","url":"https://assets-eu.researchsquare.com/files/rs-5404622/v1/4d820e5598bd4a166e2ecc67.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Association of Low Hospital Birth Volume and Adverse Short-Term Outcomes for Neonates Treated with Therapeutic Hypothermia in Rural States","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTimely identification and treatment of neonates who meet criteria for therapeutic hypothermia (TH) poses significant challenges in rural settings, where access to intensive care, neonatal specialists, and diagnostic resources may be limited. The literature is variable regarding whether outborn neonates treated with TH have more frequent adverse outcomes compared to inborn neonates. Assessing this association is challenging due various factors that are linked with being born in a non-tertiary care setting. Outborn neonates are often not resuscitated by clinicians with the same skill set and experience as neonatologists, suggesting that resuscitation practices may play a role. Outborn neonates also must be transferred from the birth hospital to the NICU, which can delay initiation of TH and make early temperature management during transport challenging(1-3). Time to reach target temperature for effective therapy can also vary and occur beyond the six-hour goal(4). Lastly, there may be differences in the overall health and pregnancy care of the mothers delivering in one setting versus the other.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMany studies have commented on the presence or absence of differences in outcomes for neonates born outside a hypothermia center, even if the study was not expressly designed to assess this question. Findings have ranged from studies that report that the majority of deaths occur in outborns(5), to a re-analysis of clinical trial data showing no difference in the benefit of therapeutic hypothermia for those who were inborn versus outborn(6, 7). However, other evidence suggests worse outcomes among outborn encephalopathic neonates with lower rates of seizure free survival(8, 9). Sabsabi et. al concluded that the level of care of the birth hospital in a metropolitan region of Canada significantly impacts outcomes, with neonates born at level one centers experiencing worse outcomes compared to neonates born at level two or three medical centers(10).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven these conflicting findings, we sought to evaluate our data from four Northern New England tertiary care centers, aiming to reconsider outborn neonates not as a single homogeneous group, but rather as a population with varying levels of risk for adverse outcomes based on the annual birth volume of their hospital of origin. We hypothesized that the risk of short-term adverse outcomes would be higher for outborn neonates transported from small (up to 500 births per year) and medium birth volume hospitals (501-1500 births per year), compared to those born in large volume hospitals (more than 1500 births per year), where TH is performed on-site. The goal of this investigation was to achieve a more nuanced understanding of the risks associated with being born in a rural setting and outcome after TH.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003e\u003cu\u003eStudy Design\u003c/u\u003e\u003c/em\u003e\u003cem\u003e:\u0026nbsp;\u003c/em\u003eA retrospective cohort study of neonates treated with TH at four tertiary care centers that participate in the Northeast Regional Hypothermia Consortium (see Supplement 1 for details about each institution).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003ePrimary Outcome:\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eThe primary outcome was in-hospital mortality or severe gray matter injury on brain MRI. Severe gray matter injury was defined by gray matter sub-score \u0026ge;9.5 per the Weeke scoring system, found to be 92% sensitive and 95% specific for an abnormal developmental outcome at 2 years defined as death, cerebral palsy (Gross Motor Function Classification System \u0026ge; II), or Bayley Scales of Infant and Toddler Development with scores \u0026lt;85(11). The gray matter injury score was assigned by a team including a neuroradiologist and a pediatric neurologist who reviewed images from all sites.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eClassification of hospitals:\u003c/u\u003e\u003c/em\u003e Hospitals were grouped according to annual birth volume. Small hospitals were defined as a birth rate of 1-500 neonates per year, medium hospitals were defined as a birth rate of 501-1500 neonates per year, and large hospitals (tertiary care centers) all had more than 1500 births per year and were also the centers where TH was implemented.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eEnvironment:\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eAt all four tertiary care centers, TH is employed for neonates who are less than six hours old at the time of initiation, are greater than or equal to 35 weeks gestation, and who have evidence of perinatal asphyxia with moderate or severe encephalopathy categorized by exam during the first six-hours of life. All four institutions maintain the 33-34\u0026deg;C temperature for 72 hours and rewarm over 12 hours with continuous EEG monitoring. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eStudy Inclusion/Exclusion Criteria:\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eNeonates were included if they were treated with TH for HIE at any of the four centers. We excluded neonates who were less than 35 weeks\u0026apos; gestation, completed less than 72 hours of TH, did not undergo brain MRI per family preference, or were transferred to a different institution due to the potential need for extracorporeal membrane oxygenation (ECMO) prior to obtaining a brain MRI. Neonates who were delivered at home or in small birthing centers were also excluded (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eDatabase:\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eData were manually extracted from the electronic medical record by trained research coordinators at each of the tertiary care centers. This study was approved by the institutional review board at each tertiary care center as exempt research.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cu\u003eStatistical Analysis:\u003c/u\u003e\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eStatistical analysis was conducted using R v.4.2.1. Baseline differences between neonates grouped according to birth volume of hospital in which they were born (small, medium and large) were compared using chi square tests or Fisher\u0026rsquo;s Exact Tests for categorical variables and t-tests or Kruskal-Wallis rank sum tests for continuous variables. A composite outcome of in-hospital mortality and gray\u0026nbsp;matter injury score \u0026ge;9.5 was created to reflect severe outcomes that differ primarily by parental decision making(12, 13). Logistic mixed effects regression analysis was performed to investigate the effect of birth hospital size on the odds of the composite outcome while controlling for possible confounders. Confounders were identified by having a statistical association with both birth volume of the hospital and the composite outcome. Covariates with just an association with the outcome (cutoff of p \u0026lt; 0.2), as well as study site were also included in the full model to improve the precision of estimates. Stepwise selection was performed on the full model using the stepAIC function from the \u003cem\u003eMASS\u003c/em\u003e package in R to achieve the most parsimonious model. A mediation analysis with 1,000 bootstrapped samples was also performed using the \u003cem\u003emediation\u0026nbsp;\u003c/em\u003epackage in R to assess the contribution of time to initiation of TH on the difference between outcomes for small versus large birth volume hospitals and medium versus large birth volume hospitals.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom 2010-2024, a total of 531 neonates were treated with TH across the four participating centers after 38 were excluded (Figure 1). Two hundred and eighteen neonates (41%) were inborn and 313 (59%) neonates were outborn. There were 120 outborn from small birth volume hospitals and 193 from medium birth volume hospitals.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMothers in small and medium birth volume hospitals were younger and had fewer medical comorbidities (Table 1). Tobacco use was highest for mothers in small birth volume hospitals, and mothers from both small and medium birth volume hospitals had higher rates of marijuana use. There were no significant differences in the rate of Cesarean section or delivery related complications, including placental abruption, cord prolapse, shoulder dystocia, or late fetal heart rate decelerations, however chorioamnionitis and uterine rupture occurred significantly more frequently in the large birth volume hospitals. Neonates in large birth volume hospitals skewed to a younger gestational age (Table 2). The umbilical cord gases demonstrated a greater degree of acidemia for neonates born in medium and large volume hospitals. There were significantly fewer cord gases collected in both small and medium birth volume hospitals. Small birth volume hospitals had the greatest proportions of neonates with mild and severe encephalopathy (Table 2).\u003c/p\u003e\n\u003cp\u003eThe frequency of seizures and severe brain injury on MRI was not statistically significantly different by hospital birth volume (Table 3). Mortality prior to hospital discharge was highest among neonates born at small birth volume hospitals (12%) compared to 3.6% and 6% for medium and high birth volume hospitals, respectively (p=0.008). The composite adverse outcome of in-hospital mortality or severe gray matter injury on MRI occurred for significantly more neonates from small birth volume hospitals (16%) compared to 6% from medium volume and 7% from large volume hospitals (p=0.002). Time to initiation of TH was significantly delayed for both small and medium hospitals, a median of 4.5 and 4 hours, respectively, compared to a median of 2 hours for large volume hospitals (p\u0026lt;0.001). \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe full regression model included severity of encephalopathy, time to initiation of TH and the interaction between these two, as well as center where hypothermia was performed, plus additional variables that differed between neonates with and without the primary outcome of death or severe grey matter injury (cesarean section, prolapsed cord, and shoulder dystocia). After stepwise selection, the final model included birth volume and encephalopathy severity. The odds of gray matter injury or death was 4.3 times higher in low birth volume compared to high birth volume hospitals (95% CI = 1.6, 12.1, p=0.004). There was no difference in odds of gray matter injury or death between medium and high birth volume hospitals (p = 0.498). Time to initiation of TH did not mediate the association between small versus large birth volume hospital and the composite outcome (p=0.946).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this analysis of neonates treated with TH in rural Northern New England, we assessed outcomes for outborns according to the annual birth volume of their hospital of origin. We found that neonates born in small birth volume hospitals compared to large birth volume hospitals have significantly higher odds of death or severe grey matter injury on brain MRI and that the delayed initiation of TH did not contribute to this difference in outcome. Contrary to our hypothesis, the odds of death or severe gray matter injury on brain MRI were not higher for neonates born in medium birth volume hospitals compared to large birth volume hospitals.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur analysis is the second to consider outborn neonates as subgroups rather than as a homogeneous entity. This type of analysis was first performed by Sabsabi et al who investigated the impact of birthplace (birth in Level I, II or III nursery) on outcome for asphyxiated neonates(10). They found a higher incidence of asphyxia for neonates born in lower care level settings (e.g. level 1 birth centers) compared to Level III centers. In multivariate analysis, birth in a level 1 birth center was associated with a 2-fold higher risk of either death or brain injury. Our results were similar, although the magnitude was higher with 4-fold increased odds of death or brain injury on MRI. One possible reason for the difference in magnitude could be that our population is primarily rural, whereas the Sabsabi study was done in an urban environment(14-16). Another possible reason could relate to the fact that the Sabsabi study was done in a country with nationalized healthcare, a system that has a known association with better outcomes(17).\u003c/p\u003e\n\u003cp\u003eSmall birth volume hospitals are intrinsically different from medium and large birth volume hospitals for several reasons. First, for small birth volume hospitals, the ability to perform an emergency Cesarean section within the standard 30-minute window may not be feasible(18). Small birth volume hospitals are also less likely to have in-house pediatrician coverage to attend deliveries. This may leave the immediate resuscitation of an asphyxiated neonate in the hands of labor and delivery staff members who may have less experience in neonatal resuscitation(19, 20). This is not the case for medium and large birth volume hospitals, which usually have around the clock coverage provided by pediatricians, pediatric hospitalists, or neonatal nurse practitioners who are more experienced in neonatal resuscitation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn a propensity score-matched analysis of neonates born in the United Kingdom, Shipley et al reported that delivery at hospitals with TH capability was associated with a greater proportion of seizure-free survival (35%), compared to delivery at centers without the ability to provide TH (31% seizure-free survival)(8). Unlike our study, the Shipley et. al. study did not appreciate a significant difference in mortality according to location of birth. This may be attributable to the fact that in the UK, TH can be performed in Level 2 and 3 centers and in this study only 14% of the study population came from Level 1 hospitals, whereas in our study nearly one-quarter of our patients are from Level-1 hospitals. In another large retrospective propensity matched analysis from the Pediatrix group, the authors also did not find a statistically significant higher rate of mortality for outborn neonates(9). However, surviving outborn neonates had significantly higher rates of seizures and gastrostomy tube placement suggesting a difference in morbidity associated with perinatal hypoxia-ischemia. The outcome measures used in these large studies were chosen as available short-term outcomes since longer term outcome measures such as formal neurodevelopmental assessments such as the Bayley Scales of Infant Development (BSID) were not available. Unfortunately, our study also did not have long term data results to analyze neurodevelopmental outcomes after hospital discharge.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTime to initiation of therapeutic hypothermia has been linked to the question of outcome differences for inborn versus outborn neonates. Neonates born outside of a TH center typically have later initiation of TH, which we observed in both small and medium birth volume hospitals in this study. The relationship of earlier time to initiation of TH with improved outcome was first highlighted in preclinical experiments(21-23). In an observational study in humans,\u0026nbsp;Thoresen et. al. demonstrated that surviving neonates with initiation of TH before three hours of life had better motor outcomes at 18-20 months compared to those with initiation after three hours(24). These data, combined with the knowledge that initiation of TH after 6 hours of life had a low probability of benefit(25)\u0026nbsp;resulted in a sense of urgency to initiate TH as quickly as possible.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMore recent work has re-assessed this urgency. A retrospective cohort of 91 Canadian born neonates assessed outcome by early (median of 1.4 hours) versus late initiation (median of 4.4 hours) of TH, no differences in the severity of brain injury on MRI or in neurodevelopmental outcomes at 18 months were appreciated(26). A recent secondary analysis of the 500 neonates enrolled in the HEAL Study(27) also did not demonstrate differences in short-term outcomes or 2-year neurodevelopmental outcomes for early (\u0026lt;4 hours) versus late (\u0026gt;4 hours) attainment of the target temperature(28). Time to initiation is confounded by the fact that neonates with severe encephalopathy tend to have TH initiated the soonest, but also have the highest rate of adverse outcome, which was why we chose to use severity of encephalopathy by time to initiation as an interaction term in our regression analysis. Additionally, the timing of the hypoxic ischemic injury onset is often not known with certainty. Our results echo these other clinical studies(26, 28) indicating that time to initiation does not affect outcome.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study has several strengths, including a unique consortium, formed by investigators from four NICUs in three of the most rural states in the United States: Maine, New Hampshire and Vermont. This novel consortium has allowed us to collect and analyze data that is not routinely available outside of major academic children\u0026apos;s hospitals. With the combination of four NICU\u0026rsquo;s, our sample size is large for data sets emerging out of rural areas and may be generalizable to other more rural locations. We used advanced statistical analyses to assess the relationship between outcome and hospital size taking into consideration both severity of encephalopathy and time to initiation of TH, as well as other potential confounders such as site. Additionally, we collected the degree of encephalopathy for all neonates in the study, and our combined outcome captures both mortality and the severe impairment expected in children with high gray matter injury scores on MRI. This combined outcome is key in our opinion as the consequence of either death or severe gray matter injury is most often the result of parental decision making rather than the inability of a neonate to survive(29). Another strength is that we chose to exclude those born in birthing centers and home births which confer a higher risk for adverse outcome(30).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are several weaknesses in this study, which include the lack of comprehensive data on longer term neurodevelopmental outcomes, and no data on time from birth to target temperature. Additionally, some data on outborn neonates was missing. For example, there were many more missing cord gases for neonates born in both small and medium birth volume hospitals, a challenge reported by others studying TH and outcomes in outborn neonates(3). There is also likely to be some residual confounding from sociodemographic variable differences for deliveries that occur in small and medium birth volume hospitals (e.g. incomplete data on drug exposure, socioeconomic status and prenatal care). This may have resulted in an overestimate of the difference in odds of adverse outcome between small and large birth volume hospitals. Finally, although each institution follows a standardized hypothermia protocol that has strong similarities between institutions, there are likely nuanced differences between institutions that are not captured by the data. We attempted to address this by controlling for site in the stepwise regression model. An additional limitation is the potential for changes in practice across time from 2010-2024. Use of a structured neonatal encephalopathy exam came into more widespread use during the epoch studied and it is very possible that intra-site differences in quality and conclusions of the exam changed during that time, particularly in differentiating mild from moderate encephalopathy.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis analysis evaluated neonates treated with therapeutic hypothermia from three rural states and separated the neonates that were treated with TH into subgroups based on the birth volume of the hospital of origin. We found that births in small compared to large birth volume hospitals have significantly higher odds of death or severe gray matter injury on MRI. This was not the case for medium volume hospitals, and our results did not show an effect of time to initiate TH on outcome. Further analysis is needed to delineate the obstetric and neonatal resuscitation factors that may be involved in our finding of increased morbidity and mortality associated with lower birth volume hospitals in these three rural states. Potential strategies to support neonatal resuscitation and stabilization may be needed in these small, often critical access rural community hospitals. The use of telehealth modalities may facilitate interactions between expert subspecialists and primary care providers in these efforts to improve outcomes.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eEEG Electroencephalogram\u003c/p\u003e\n\u003cp\u003eHIE Hypoxic Ischemic Encephalopathy\u003c/p\u003e\n\u003cp\u003eMMC Maine Medical Center\u003c/p\u003e\n\u003cp\u003eMRI Magnetic resonance imaging \u003c/p\u003e\n\u003cp\u003eNE Neonatal Encephalopathy\u003c/p\u003e\n\u003cp\u003eNICU Neonatal Intensive Care Unit\u003c/p\u003e\n\u003cp\u003eNLEMMC Northern Light Eastern Maine Medical Center\u003c/p\u003e\n\u003cp\u003eTH Therapeutic hypothermia\u003c/p\u003e\n\u003cp\u003eUVMMC University of Vermont Medical Center\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding Sources:\u003c/strong\u003e Dr. Craig, Ms. Cutler and Ms. Seften were supported by grant 1P20GM139745-01 from the National Institutes of Health for the Center of Biomedical Research Excellence in Acute Care Research and Rural Disparities. Dr. Craig and the REDCap administrator were also supported by U54 GM115516 from the Northern New England Clinical and Translational Research network which funds the MaineHealth instance of REDCap.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosure\u003c/strong\u003e: The authors have no conflicts of interest to disclose. \u0026nbsp;\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe authors thank the individuals who contributed to data collection; Megan Berube, MD, Leah Fox, MD, Lauren McAllister, MD, and Sophi Aronson from MMC as well as Emily Fraser-Read. Delaney Davis, and Krysta Anderson from NLEMMC and Jessica Moya from Elliot Hospital. Melanie Parziale, MD from The University of Vermont, Larner College of Medicine.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010;30(5):324-9.\u003c/li\u003e\n\u003cli\u003eO\u0026apos;Reilly D, Labrecque M, O\u0026apos;Melia M, Bacic J, Hansen A, Soul JS. Passive cooling during transport of asphyxiated term newborns. J Perinatol. 2013;33(6):435-40.\u003c/li\u003e\n\u003cli\u003eHarbert MJA, Sey R, Arnell K, Rasmussen M. Identifying Ways to Fix Outcome Disparities among Outborns Needing Therapeutic Hypothermia. Am J Perinatol. 2021;38(S 01):e21-e5.\u003c/li\u003e\n\u003cli\u003eSimbruner G, Mittal RA, Rohlmann F, Muche R, neo.n EnTP. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010;126(4):e771-8.\u003c/li\u003e\n\u003cli\u003eEicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005;32(1):11-7.\u003c/li\u003e\n\u003cli\u003eNatarajan G, Pappas A, Shankaran S, Laptook AR, Walsh M, McDonald SA, et al. Effect of inborn vs. outborn delivery on neurodevelopmental outcomes in infants with hypoxic-ischemic encephalopathy: secondary analyses of the NICHD whole-body cooling trial. Pediatr Res. 2012;72(4):414-9.\u003c/li\u003e\n\u003cli\u003eThayyil S, Montaldo P, Krishnan V, Ivain P, Pant S, Lally PJ, et al. Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities: A Nested Study Within a Randomized Clinical Trial. JAMA Netw Open. 2023;6(5):e2312152.\u003c/li\u003e\n\u003cli\u003eShipley L, Mistry A, Sharkey D. Outcomes of neonatal hypoxic-ischaemic encephalopathy in centres with and without active therapeutic hypothermia: a nationwide propensity score-matched analysis. Arch Dis Child Fetal Neonatal Ed. 2022;107(1):6-12.\u003c/li\u003e\n\u003cli\u003eStetson RC, Brumbaugh JE, Weaver AL, Mara KC, Clark RH, Carey WA, et al. Association of outborn versus inborn birth status on the in-hospital outcomes of neonates treated with therapeutic hypothermia: A propensity score-weighted cohort study. Resuscitation. 2021;167:82-8.\u003c/li\u003e\n\u003cli\u003eSabsabi B, Huet C, Rampakakis E, Beltempo M, Brown R, Lodygensky GA, et al. Asphyxiated Neonates Treated with Hypothermia: Birth Place Matters. Am J Perinatol. 2022;39(3):298-306.\u003c/li\u003e\n\u003cli\u003eWeeke LC, Groenendaal F, Mudigonda K, Blennow M, Lequin MH, Meiners LC, et al. A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia. J Pediatr. 2018;192:33-40 e2.\u003c/li\u003e\n\u003cli\u003eNatarajan G, Mathur A, Zaniletti I, DiGeronimo R, Lee KS, Rao R, et al. Withdrawal of Life-Support in Neonatal Hypoxic-Ischemic Encephalopathy. Pediatr Neurol. 2019;91:20-6.\u003c/li\u003e\n\u003cli\u003eWilkinson D. MRI and withdrawal of life support from newborn infants with hypoxic-ischemic encephalopathy. Pediatrics. 2010;126(2):e451-8.\u003c/li\u003e\n\u003cli\u003eLisonkova S, Haslam MD, Dahlgren L, Chen I, Synnes AR, Lim KI. Maternal morbidity and perinatal outcomes among women in rural versus urban areas. CMAJ : Canadian Medical Association journal = journal de l\u0026apos;Association medicale canadienne. 2016;188(17-18):E456-E65.\u003c/li\u003e\n\u003cli\u003eEly DM, Hoyert DL. Differences Between Rural and Urban Areas in Mortality Rates for the Leading Causes of Infant Death: United States, 2013-2015. NCHS Data Brief. 2018(300):1-8.\u003c/li\u003e\n\u003cli\u003eEhrenthal DB, Kuo HD, Kirby RS. Infant Mortality in Rural and Nonrural Counties in the United States. Pediatrics. 2020;146(5).\u003c/li\u003e\n\u003cli\u003eWeaver MR, Nandakumar V, Joffe J, Barber RM, Fullman N, Singh A, et al. Variation in Health Care Access and Quality Among US States and High-Income Countries With Universal Health Insurance Coverage. JAMA Netw Open. 2021;4(6):e2114730.\u003c/li\u003e\n\u003cli\u003eMooney SE, Ogrinc G, Steadman W. Improving emergency caesarean delivery response times at a rural community hospital. Quality \u0026amp; safety in health care. 2007;16(1):60-6.\u003c/li\u003e\n\u003cli\u003eJukkala AM, Henly SJ. Provider readiness for neonatal resuscitation in rural hospitals. J Obstet Gynecol Neonatal Nurs. 2009;38(4):443-52.\u003c/li\u003e\n\u003cli\u003eZanno A, Melendi M, Cutler A, Stone B, Chipman M, Holmes J, et al. Simulation-Based Outreach Program Improves Rural Hospitals\u0026apos; Team Confidence in Neonatal Resuscitation. Cureus. 2022;14(9):e28670.\u003c/li\u003e\n\u003cli\u003eGunn AJ, Bennet L, Gunning MI, Gluckman PD, Gunn TR. Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep. Pediatr Res. 1999;46(3):274-80.\u003c/li\u003e\n\u003cli\u003eGunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997;99(2):248-56.\u003c/li\u003e\n\u003cli\u003eIwata O, Iwata S, Tamura M, Nakamura T, Sugiura M, Ogiso Y, et al. Early head cooling in newborn piglets is neuroprotective even in the absence of profound systemic hypothermia. Pediatrics international : official journal of the Japan Pediatric Society. 2003;45(5):522-9.\u003c/li\u003e\n\u003cli\u003eThoresen M, Tooley J, Liu X, Jary S, Fleming P, Luyt K, et al. Time is brain: starting therapeutic hypothermia within three hours after birth improves motor outcome in asphyxiated newborns. Neonatology. 2013;104(3):228-33.\u003c/li\u003e\n\u003cli\u003eLaptook AR, Shankaran S, Tyson JE, Munoz B, Bell EF, Goldberg RN, et al. Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial. JAMA. 2017;318(16):1550-60.\u003c/li\u003e\n\u003cli\u003eGuillot M, Philippe M, Miller E, Davila J, Barrowman NJ, Harrison MA, et al. Influence of timing of initiation of therapeutic hypothermia on brain MRI and neurodevelopment at 18 months in infants with HIE: a retrospective cohort study. BMJ Paediatr Open. 2019;3(1):e000442.\u003c/li\u003e\n\u003cli\u003eWu YW, Comstock BA, Gonzalez FF, Mayock DE, Goodman AM, Maitre NL, et al. Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns. N Engl J Med. 2022;387(2):148-59.\u003c/li\u003e\n\u003cli\u003eRao R, Comstock BA, Wu TW, Mietzsch U, Mayock DE, Gonzalez FF, et al. Time to Reaching Target Cooling Temperature and 2-year Outcomes in Infants with Hypoxic-Ischemic Encephalopathy. J Pediatr. 2024;266:113853.\u003c/li\u003e\n\u003cli\u003eLemmon ME, Bonifacio SL, Shellhaas RA, Wusthoff CJ, Greenberg RG, Soul JS, et al. Characterization of Death in Infants With Neonatal Seizures. Pediatr Neurol. 2020;113:21-5.\u003c/li\u003e\n\u003cli\u003eSnowden JM, Tilden EL, Snyder J, Quigley B, Caughey AB, Cheng YW. Planned Out-of-Hospital Birth and Birth Outcomes. N Engl J Med. 2015;373(27):2642-53.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1: Characteristics of Birth Parent and Delivery by Hospital Birth Volume\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"634\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0-500\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 120\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e501-1500\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 193\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e1501+\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 218\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMaternal Age\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29.0 (23.0, 32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30.0 (24.0, 33.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e31.0 (26.0, 34.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGestational Diabetes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e28 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePreeclampsia/Eclampsia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (6.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.053\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMultiple Gestation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (0.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12 (5.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTobacco\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16 (8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17 (7.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.021\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOpioids\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 (5.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16 (7.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSSRIs\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBenzodiazepines\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1 (0.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (0.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMarijuana\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.013\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMaternal fever\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (4.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e14 (6.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGBS positive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e56 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eChorioamnionitis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e32 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eProlonged Rupture of Membranes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eLate Decelerations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e26 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eC-Section\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e63 (52%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e98 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e120 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eShoulder Dystocia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (9.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19 (9.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eProlapsed Cord\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3 (2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (2.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ePlacental Abruption\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (7.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18 (8.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eUterine Rupture\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4 (2.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e10 (4.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.03\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e Median (IQR); n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e Kruskal-Wallis rank sum test; Pearson\u0026apos;s Chi-squared test; Fisher\u0026apos;s exact test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2: Characteristics of Newborns by Hospital Birth Volume\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"634\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0-500\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 120\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e501-1500\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 193\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e1501+\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 218\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGestational Age\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.00 (38.00, 40.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.00 (38.00, 40.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39.00 (37.00, 40.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eGestational Age \u0026lt;37 wks\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e18 (9.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e33 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBirth Weight (kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.40 (3.00, 3.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.35 (2.96, 3.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.27 (2.89, 3.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMale Sex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e65 (54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e109 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e125 (57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAPGAR 1 min\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (1, 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (1, 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 (1, 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Not documented\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAPGAR 5 min\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4. (3, 5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (3, 7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5 (3, 6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Not documented\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eAPGAR 10 min\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (4, 7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (5, 8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 (5, 7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Not documented\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eArterial Cord pH\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.15 (7.02, 7.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.08 (6.96, 7.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.07 (6.94, 7.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.005\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Not collected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eVenous Cord pH\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.23 (7.07, 7.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.19 (7.07, 7.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.22 (7.08, 7.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026gt;0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Not collected\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSeverity of HIE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Mild\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Moderate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e76(63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e146 (76%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e169 (78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Severe\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e25 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e Median (IQR); n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e Kruskal-Wallis rank sum test; Pearson\u0026apos;s Chi-squared test; Fisher\u0026apos;s exact test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3: Short-term Outcomes of Newborns by Hospital Birth Volume\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"634\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e0-500\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 120\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e501-1500\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 193\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003e1501+\u003c/strong\u003e,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eN = 218\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDeath\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (3.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (6.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.008\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSevere grey matter injury\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDeath or severe grey matter injury\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e11 (6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSeizure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e53 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e46 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eTime to TH Initiation in\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ehours (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.50 (3.00, 5.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.00 (3.00, 5.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.00 (1.00, 3.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e1\u003c/sup\u003e\u003c/em\u003e Median (IQR); n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003e\n \u003cp\u003e\u003cem\u003e\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e Kruskal-Wallis rank sum test; Pearson\u0026apos;s Chi-squared test; Fisher\u0026apos;s exact test\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5404622/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5404622/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e We hypothesized that outborn neonates from smaller birth volume hospitals would have more frequent adverse short-term outcomes following therapeutic hypothermia (TH).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design:\u003c/strong\u003eMulticenter retrospective study comparing outcomes for small (\u0026lt;500 births/year), medium (501-1500 births/year), and large (\u0026gt;1500 births/year) hospitals in Northern New England. Multivariable logistic regression assessed the combined outcome of death/severe gray matter injury on MRI, controlling for encephalopathy severity and time to initiation of TH.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e 531 neonates were included from small (N=120), medium (N=193), and large (N=218) volume hospitals and TH was initiated at a median of 4.5, 4, and 2 hours of life respectively. The odds of the combined outcome were 4.3-fold higher in small versus large birth volume hospitals (95% CI = 1.6, 12.1, p=0.004), but not different in medium birth volume hospitals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Neonates born in small volume hospitals had significantly higher odds of death or severe gray matter injury following TH.\u003c/p\u003e","manuscriptTitle":"Association of Low Hospital Birth Volume and Adverse Short-Term Outcomes for Neonates Treated with Therapeutic Hypothermia in Rural States","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-18 15:48:34","doi":"10.21203/rs.3.rs-5404622/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-01-10T13:17:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-11-20T22:19:09+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-15T14:35:57+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-11-15T14:12:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-12T11:56:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2024-11-11T17:12:02+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2024-11-07T11:10:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-06T17:13:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ed2f1a65-9681-4a9e-b3fc-d941c55bdb7e","owner":[],"postedDate":"December 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":40322076,"name":"Health sciences/Diseases/Neurological disorders/Brain injuries"},{"id":40322077,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-07-06T07:05:21+00:00","versionOfRecord":{"articleIdentity":"rs-5404622","link":"https://doi.org/10.1038/s41372-025-02352-8","journal":{"identity":"journal-of-perinatology","isVorOnly":false,"title":"Journal of Perinatology"},"publishedOn":"2025-07-06 04:00:00","publishedOnDateReadable":"July 6th, 2025"},"versionCreatedAt":"2024-12-18 15:48:34","video":"","vorDoi":"10.1038/s41372-025-02352-8","vorDoiUrl":"https://doi.org/10.1038/s41372-025-02352-8","workflowStages":[]},"version":"v1","identity":"rs-5404622","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5404622","identity":"rs-5404622","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}