BACKGROUND:Packed red blood cell (pRBC) transfusions are often required in extremely premature infants but are associated with increased pro-inflammatory cytokines and adverse neurodevelopment, which may differ by sex. METHODS:In this post-hoc analysis of the Preterm Erythropoietin Neuroprotection (PENUT) Trial, associations between pRBC transfusion volume and cytokines at 0-7 and 7-14 days, MRI injury, and Bayley Scales of Infant Development (BSID-III) scores at 24 months corrected age were evaluated. Graphical network and generalized estimating equation models were used to examine interactions by sex as well as the influence of hematocrit level. RESULTS:182 and 164 infants were assessed with biomarkers at 0-7 and 7-14 days, 220 infants had MRIs, and 692 infants had at least one BSID-III assessment. Infant sex modified the association between pRBC transfusion volume and IL-6 at 7-14 days but did not impact the association between transfusion volume or hematocrit and BSID-III scores. Total pRBC transfusion volume was significantly negatively associated with all BSID-III subscales after accounting for anemia and severity of illness. CONCLUSION:Infant sex may impact short-term cytokine responses to transfusions but not the association between transfusion volume and long-term outcomes. IMPACT:In a post hoc analysis of extremely preterm infants from the PENUT Trial, the relationship between transfusion exposure and pro-inflammatory cytokines, MRI scores and neurodevelopment were evaluated by sex. The impact of transfusions on inflammatory cytokines may vary by sex. However, this does not appear to lead to differences in neurodevelopmental outcomes. Based on current evidence, providers should not alter their transfusion practices based on sex of the infant.

Background/Objective(s): Post-discharge clinical needs of extremely preterm (EP) infants are not well defined. The aim of this study is to evaluate healthcare utilization after discharge in infants born EP and compare it to the general pediatric population. Methods: This study involved a post hoc analysis of infants born 24-0/7 to 27-6/7 weeks’ gestation enrolled in the Preterm Erythropoietin Neuroprotection (PENUT) Trial who had at least one follow-up survey representing their course between 24 and 60 months of age. The results were compared to the general population data from the Kids’ Inpatient Database, Nationwide Emergency Department Sample, and National Health and Nutrition Examination Survey. Results: Maternal, infant, and hospitalization characteristics for PENUT infants who survived to discharge (n = 828) compared to those with follow-up (n = 569) were similar except for race and maternal age. Overall, EP infants had an overall lower rate of ED visits (31% vs. 68%) but a higher rate of hospitalizations (11% vs. 3%). EP infants were less likely to go to the ED for gastrointestinal (5% vs. 12%) and dermatologic (1% vs. 6%) concerns but more likely to go to the ED for procedures (7% vs. <1%). EP infants had a higher rate of medication use (56% vs. 14%) in all categories except psychiatric medications. Conclusions: While EP infants had higher rates of specialty healthcare utilization relative to the general pediatric population, they were less likely to visit the ED overall, particularly for common concerns in this age range. This may reflect improved access and navigation of the healthcare system by EP caregivers.

Background/Objectives: Magnesium sulfate (MgSO4) has historically been used in obstetrics as a tocolytic and to prevent eclamptic seizures. MgSO4 has also been investigated as a potential neonatal neuroprotectant for infants born preterm. However, randomized controlled trials of prenatal MgSO4 have shown mixed results, with single-center observational studies also suggesting differential effects by sex. We sought to evaluate sex-dependent associations between prenatal MgSO4 exposure and standardized neurodevelopmental outcomes in a large, multi-center cohort of extremely preterm neonates (24-0/7 to 27-6/7 weeks' gestation) from the Preterm Erythropoietin Neuroprotection Trial (PENUT). Methods: The relationship between maternal MgSO4 exposure and neurodevelopmental outcomes assessed at 2 years using the Bayley Scales of Infant and Toddler Development Index, 3rd edition was examined by sex in n = 666 infants (n = 328 female, n = 338 male). To account for confounding by indication, we performed both matching and inverse probability weighting using 17 maternal predictors of MgSO4 exposure. Results: In both unadjusted and adjusted (weighted and matched) analyses, no relationship between MgSO4 exposure and neurodevelopmental outcomes was seen, either overall or by sex. Conclusions: This study reaffirms the safety of MgSO4, but appropriate clinical trials of MgSO4 in extremely preterm infants are still required to better understand any effects on neurodevelopmental outcomes.

Explore the effect of a 6-week online program of yogic breathing, meditation, and gentle postures for parents of infants hospitalized in the neonatal intensive care unit (NICU).From October 2021 to October 2023, we conducted a two-center pilot study of yoga for NICU parents. We assigned consented parents of NICU inpatients to receive yoga classes (YG) and/or usual care (UC) for parent support within 14 days of admission to the NICU. Self-directed yoga sessions were completed using an online platform. UC included parental support as practiced in each NICU and served as a control group. Primary outcomes were assessed at the study entrance, midpoint, and conclusion using the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS: NICU) and the Postpartum Bonding Questionnaire (PBQ) in English and Spanish.A total of n = 51 parents (71%) mothers, were allocated using parallel assignment to UC (n = 28, 55%) or YG (n = 23, 45%). A total of n = 39 (76%) parents completed the classes to the midpoint of the study and n = 33 (65%) completed all 6 weeks of the study. There were no differences in baseline characteristics for parents or infants between groups. Average participation in the online yoga materials was 3 hours and 45 minutes per parent. A significant decrease in NICU-related parent stress emerged for all PSS: NICU subscales and total PSS: NICU scores for parents assigned to YG between enrollment and the midpoint of the study. Neither parents in UC nor YG approached thresholds indicating disorders of the parent-infant relationship as assessed by the PBQ.When initiated early, an online, asynchronous yoga intervention designed for parents may reduce NICU parent stress. · Yoga may reduce stress and enhance emotional health for parents of critically ill newborns.. · Virtual and self-directed mindfulness interventions for parents are feasible in the NICU environment.. · Sustaining parental wellness over an extended NICU hospitalization is challenging..

Time to regain birthweight (time-to-regain) includes subcomponents of time from birth to weight loss nadir (birth-to-nadir), time from weight loss nadir to regain birthweight (nadir-to-regain), and cumulative weight loss (CWL; sum of daily percent weight loss from birthweight until regain), yet relationship with in-hospital outcomes remains unknown. We performed a secondary analysis of the multicenter Preterm Erythropoietin Neuroprotection (PENUT) Trial including extremely preterm (EP) newborns at 24w0d-27w6d gestation at birth evaluating time-to-regain and its subcomponents with in-hospital adverse outcomes. Among n = 876 EP newborns, time-to-regain was not significantly associated with in-hospital outcomes. CWL had a U-shaped distribution with >2.5-fold increased odds of NEC for those without weight loss and moderate or severe CWL when compared with mild CWL (>0 to −23 percent-days). Increasing birth-to-nadir was associated with increased odds of NEC (linear trend analysis aOR 1.33, 95 https://clinicaltrials.gov/ct2/show/NCT01378273 .

Objective: To explore the effect of a 6-week online program of yogic breathing, meditation, and gentle postures for parents of infants hospitalized in the neonatal intensive care unit (NICU). Study Design: From Oct 2021 to Oct 2023, we conducted a two-center pilot study of yoga for NICU parents. We assigned consented parents of NICU inpatients to receive yoga classes (YG) and/or usual care for parent support (UC) within 14 days of admission to the NICU. Self-directed yoga sessions were completed using an online platform. Usual care included parental support as practiced in each NICU and served as a control group. Primary outcomes were assessed at study entrance, midpoint and conclusion using the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS: NICU) and the Postpartum Bonding Questionnaire (PBQ) in English and Spanish. Results: N=51 parents (71%) mothers were allocated using parallel assignment to UC (N=28, 55%) or YG (N=23, 45%). A total of N=39(76%) parents completed the classes to the midpoint of the study and N=33(65%) completed all 6-weeks of the study. There were no differences in baseline characteristics for parents or infants between groups. Average participation in the online yoga materials was 3hrs 45min per parent. A significant decrease in NICU related parent stress emerged for all PSS: NICU subscales and total PSS: NICU score for parents assigned to YG between enrollment and the midpoint of the study. Neither parents in UC nor YG approached thresholds indicating disorders of the parent-infant relationship as assessed by the postpartum bonding questionnaire. Conclusion: When initiated early, an online, asynchronous yoga intervention designed for parents may reduce NICU parent stress.

Infants born preterm are at high risk of anemia, red blood cell transfusions, and iron deficiency, all of which may negatively influence long-term neurodevelopment. To ameliorate these complications of prematurity, we developed a Phase II trial to determine whether treatment with an erythropoietic-stimulating agent, darbepoetin (Darbe), plus a slow-release intravenous (IV) iron preparation (ferumoxytol (FMX) or low-molecular-weight iron dextran (LMW-ID)) might decrease transfusions while maintaining iron sufficiency. This single-center study is a parallel design, prospective, randomized controlled Phase II trial of 120 infants born 24–0/7 to 31–6/7 weeks of gestation cared for in the University of Washington Neonatal Intensive Care Unit. After informed consent, infants less than 72 h of age are randomized to one of five treatment groups: (1) Oral iron (standard care), n = 40, or weekly Darbe 10 µg/kg/dose IV or SQ plus; (2) FMX — 10 mg/kg/dose IV, n = 20; (3) FMX — 20 mg/kg/dose IV, n = 20; (4) LMW-ID — 10 mg/kg/dose IV, n = 20; or (5) LMW-ID — 20 mg/kg/dose IV, n = 20. Infants will be followed to 2-year corrected age with sequential developmental testing. Our primary outcome is ferritin level at 34–36 weeks postmenstrual age. Secondary outcomes include other hematologic assessments, drug safety, evaluation of the gut microbiome, and neurodevelopment to 2 years corrected age. This trial will determine whether darbepoetin plus a slow-release IV iron preparation is safe, which iron preparation and dose best maintain iron sufficiency and decrease or eliminate transfusions, whether IV iron will result in a more diverse, less pathogenic microbiome when compared to oral iron supplementation, and, finally, whether these treatments affect neurodevelopment to 2 years corrected age. National Clinical Trial (NCT) NCT05340465. Registered on March 1, 2022.

Background: The relationship between early antibiotic exposure, necrotizing enterocolitis (NEC), and growth faltering (GF) in extremely preterm infants is unknown. Methods: We evaluated the association between peripartum and postnatal antibiotic exposure in the first week after birth with NEC and GF in this secondary analysis of Preterm Erythropoietin Neuroprotection Trial subjects. NEC was defined as Bell's stage >= IIA; GF was defined as decreased weight, length, or head circumference (HC) z-score from birth to discharge of < -0.8. Multivariable analyses were adjusted with maternal and infant factors. Results: A total of 891 infants survived the first week and were included in the NEC analyses, while 828 infants survived to discharge and were included in the growth analyses. For every 1-day increase in infant antibiotic exposure during the first week after birth, there was a significantly increased adjusted hazard of NEC (aHR/day 1.14 [1.01-1.28], p = 0.034). Antibiotics for 3-4 days and 5-7 days total in the first week were associated with increased odds of weight GF (aOR 1.90 [1.21-2.99], aOR 2.32 [1.44-3.74]), length GF (aOR 1.76 [1.22-2.59], aOR 1.88 [1.26-2.80]), and HC GF (aOR 1.75 [1.08-2.84], aOR 1.87 [1.14-3.08]). Conclusion: Increased antibiotic exposure in the first week after birth was associated with NEC and GF risk. Impact: center dot In this post-hoc analysis of a large multi-site trial, we found infant antibiotic exposure in the first week after birth was associated with an increased hazard of necrotizing enterocolitis in the extremely preterm infant after adjusting for maternal and infant factors. center dot First week antibiotic exposure in the extremely preterm infant was associated with an increased odds of weight, linear, and head circumference growth faltering after adjusting for maternal and infant factors. center dot These findings encourage the judicious use of early antibiotics in extremely preterm infants.

BackgroundBoth perinatal arterial ischemic stroke (PAIS) and hypoxic-ischemic encephalopathy (HIE) can present with neonatal encephalopathy. We hypothesized that among infants undergoing therapeutic hypothermia, presence of PAIS is associated with a higher risk of seizures and a lower risk of persistent encephalopathy after rewarming.MethodsWe studied 473 infants with moderate or severe HIE enrolled in the HEAL Trial who received a brain MRI. We defined PAIS as focal ischemic infarct(s) within an arterial distribution, and HIE pattern of brain injury as central gray, peripheral watershed, or global injury. We compared the risk of seizures (clinically suspected or electrographic), and of an abnormal 5-day Sarnat exam, in infants with and without PAIS.ResultsPAIS was diagnosed in 21(4%) infants, most of whom (16/21, 76%) also had concurrent HIE pattern of brain injury. Infants with PAIS were more likely to have seizures (RR 2.4, CI 2.8-3.3) and persistent moderate or severe encephalopathy on 5-day Sarnat exam (RR 2.5, 95% CI 1.9-3.4).ConclusionAmong infants undergoing therapeutic hypothermia, PAIS typically occurs with concurrent HIE pattern brain injury. The higher rate of encephalopathy after rewarming in infants with PAIS may be due to the frequent co-existence of PAIS and HIE patterns of injury.

BACKGROUND:Associations of 2-year neurodevelopmental and behavioral outcomes with growth trajectories of preterm infants are unknown. METHODS:This secondary analysis of a preterm cohort examined in-hospital and discharge to 2-year changes in anthropometric z-scores. Two-year follow-up included Bayley Scales of Infant Development (BSID-III) and Child Behavior Checklist. RESULTS:Among 590 infants, adjusted in-hospital growth was not associated with any BSID-III subscale. Occipitofrontal circumference (OFC) growth failure (GF) in-hospital was associated with increased adjusted odds of attention problems (aOR 1.65 [1.03, 2.65]), aggressive behavior (aOR 2.34 [1.12, 4.89]), and attention-deficit-hyperactivity symptoms (aOR 1.86 [1.05, 3.30]). Infants with OFC GF at 2 years had lower adjusted BSID-III language scores (-4.0 [-8.0, -0.1]), increased odds of attention problems (aOR 2.29 [1.11, 4.74]), aggressive behavior (aOR 3.09 [1.00, 9.56]), and externalizing problems (aOR 3.01 [1.07, 8.45]) compared to normal OFC growth cohort. CONCLUSION:Infants with OFC GF are at risk for neurodevelopmental and behavioral impairment. CLINICAL TRIAL REGISTRATION:This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273.

OBJECTIVE:To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN:This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS:Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS:Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

ObjectiveWe determined the frequency of previously unsuspected genetic or congenital anomalies in infants with HIE, and whether such anomalies are associated with neurodevelopmental outcome.MethodsInfants with moderate or severe HIE enrolled in a phase III randomized controlled trial (HEAL) underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at two years of age by a standardized neurologic examination, Bayley Scales of Infant Development-III (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive and language scores at age 2 years.ResultsOf 500 infants with HIE, 24 (5%, 95% CI 3-7%) were diagnosed with a genetic (n=15) or congenital (n=14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on neonatal EEG and brain MRI. However, infants with genetic or congenital anomalies were more likely to have the primary outcome of death or NDI (75% vs 50%, P= 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs. 13%, p =0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies.ConclusionAmong infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

ObjectiveTo study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE).DesignSecondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves.SettingRandomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA.Patients479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE).InterventionsStandardised SE was used across sites before and after TH. All providers underwent standardised SE training.Main outcome measuresPrimary outcome was defined as the composite outcome of death or any NDI at 22-36 months.ResultsBoth qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe.ConclusionBoth rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

Determine association between time to regain birthweight and 2-year neurodevelopment among extremely preterm (EP) newborns. Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating time to regain birthweight, time from birth to weight nadir, time from nadir to regain birthweight, and cumulative weight loss with 2-year corrected Bayley Scales of Infant and Toddler Development 3rd edition. Among n = 654 EP neonates, those with shorter nadir-to-regain had lower cognitive scores (≤1 day versus ≥8 days: −5.0 points, [CI −9.5, −0.6]) and lower motor scores (≤1 day versus ≥8 days: −4.6 points [CI −9.2, −0.03]) in adjusted stepwise forward regression modeling. Increasingly cumulative weight loss was associated with lower cognitive scores (≤−50 percent-days: −5.6, [CI −9.4, −1.8]), motor scores (≤−50 percent-days: −4.2, [CI -8.2, -0.2]); and language scores (≤−50 percent-days: −6.0, [CI −10.1, −1.9]). Faster nadir-to-regain and excessive cumulative weight loss are associated with adverse 2-year neurodevelopmental outcomes. PENUT Trial Registration: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 . This study is a post-hoc secondary analysis of pre-existing data from the PENUT Trial (NCT #01378273).

Relief of human suffering is one of the most important goals of all healthcare providers. Advances in neonatology have significantly reduced neonatal morbidity and mortality, but pain, discomfort, and stress remain sad realities for babies in the neonatal intensive care unit (NICU). Assessing, managing, and trying to limit these clinical realities, particularly while caring for critically ill neonates, remain challenging and increasingly controversial. Fortunately, considerable clinical and laboratory research and clinical dialogue continue to push neonatal providers toward best clinical practices in this problematic arena. This chapter describes the history, developmental biology, and public policies that have informed and shaped current clinical practices; it also summarizes relevant clinical and basic research regarding clinical assessment tools and both pharmacologic and nonphar¬macologic management approaches. Finally, future directions in this field are suggested.

Aim: To explore NICU parent and staff attitudes towards yoga for parents as a stress reduction intervention and determine the acceptability of an online yoga curriculum. Methods: A 13-item survey on yoga for parents was emailed to clinical and non-clinical staff at two level IV NICUs. Another 40-item survey was distributed to parents via linked QR code in both units. Results were used to determine feasibility of a 6-week online yoga curriculum for NICU parents. Results: 54 parent and 140 staff surveys were completed between Jan 2021-Mar 2022. Many NICU parents self-reported stress (n=40, 74%) and anxiety (n=35, 64%). Thirty-seven (68%) parents had practiced yoga and 13% used yoga as a coping strategy. A total of 114 (81%) staff members practiced yoga and thought yoga decreased stress (n=125, 89%) and anxiety (n=100, 71%). Most responders (97%) with any experience with yoga supported a yoga intervention for parents. 71% of parents supported online classes. Identified barriers from staff included liability (n=28, 20%), cost (n=30, 21%) and safety (n=44, 31%). Parents cited stress (n=1,17%), lack of time (n=2, 33%) and inexperience (n=1,17%) as barriers. Conclusion: Online yoga classes may be an innovative approach to address parental stress and anxiety during NICU hospitalization.

To explore parent and staff attitudes towards yoga for neonatal intensive care unit (NICU) parents as a stress reduction intervention and determine the acceptability of an online yoga curriculum. A 13-item survey regarding attitudes about yoga as a stress reduction intervention for NICU parents was emailed to clinical and non-clinical staff at two level IV NICUs. Another 40-item survey was distributed to parents via linked QR code in both units. Results were used to determine acceptability of a 6-week online yoga curriculum for NICU parents. 54 parent and 140 staff surveys were completed between Jan 2021–Mar 2022. Many NICU parents self-reported stress (n = 40, 74%) and anxiety (n = 35, 64%). Thirty-seven (68%) parents had practiced yoga and 13% used yoga as a coping strategy. A total of 114 (81%) staff members practiced yoga and thought yoga decreased stress (n = 125, 89%) and anxiety (n = 100, 71%). Most responders (97%) with any experience with yoga supported a yoga intervention for parents. 71% of parents supported online classes. Identified barriers from staff included liability (n = 28, 20%), cost (n = 30, 21%) and safety (n = 44, 31%). Parents cited stress (n = 1,17%), lack of time (n = 2, 33%) and inexperience (n = 1,17%) as barriers. Online yoga classes may be an innovative approach to address parental stress and anxiety during NICU hospitalization. Many parents of critically ill infants in the NICU suffer from stress and anxiety. This study suggests that an online yoga curriculum for NICU parents is acceptable to parents and hospital staff and may provide an innovative non-pharmacologic approach to address parent stress and anxiety.

Objective: We aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelopmental impairment (NDI) at 2 years of age after undergoing therapeutic hypothermia compared to subjects without acute placental changes. Study Design: Among 500 subjects born at ≥36 weeks gestation with moderate or severe HIE enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, a placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute only, chronic only, or both acute and chronic histologic abnormalities. We calculated adjusted relative risks (aRRs) for associations between placental pathologic abnormalities and death or NDI at age 2 years, adjusting for HIE severity, treatment assignment, and site. Result: 321/500 subjects (64%) had available placental pathology reports. Placental abnormalities were characterized as acute only (20%), chronic only (21%), both acute and chronic (43%), and none (15%). The risk of death or NDI was not statistically different between subjects with and without an acute placental abnormality (46 vs. 53%, aRR 1.1, 95% confidence interval (CI): 0.9, 1.4). Subjects with two or more chronic lesions were more likely to have an adverse outcome than subjects with no chronic abnormalities, though this did not reach statistical significance (55 vs. 45%, aRR 1.24, 95% CI: 0.99, 1.56). Conclusion: Placental pathologic findings were not independently associated with risk of death or NDI in subjects with HIE. The relationship between multiple chronic placental lesions and HIE outcomes deserves further study.

OBJECTIVES:In infants with hypoxic-ischemic encephalopathy (HIE), conflicting information on the association between early glucose homeostasis and outcome exists. We characterized glycemic profiles in the first 12 hours after birth and their association with death and neurodevelopmental impairment (NDI) in neonates with moderate or severe HIE undergoing therapeutic hypothermia. METHODS:This post hoc analysis of the High-dose Erythropoietin for Asphyxia and Encephalopathy trial included n = 491 neonates who had blood glucose (BG) values recorded within 12 hours of birth. Newborns were categorized based on their most extreme BG value. BG >200 mg/dL was defined as hyperglycemia, BG <50 mg/dL as hypoglycemia, and 50 to 200 mg/dL as euglycemia. Primary outcome was defined as death or any NDI at 22 to 36 months. We calculated odds ratios for death or NDI adjusted for factors influencing glycemic state (aOR). RESULTS:Euglycemia was more common in neonates with moderate compared with severe HIE (63.6% vs 36.6%; P < .001). Although hypoglycemia occurred at similar rates in severe and moderate HIE (21.4% vs 19.5%; P = .67), hyperglycemia was more common in severe HIE (42.3% vs 16.9%; P < .001). Compared with euglycemic neonates, both, hypo- and hyperglycemic neonates had an increased aOR (95% confidence interval) for death or NDI (2.62; 1.47-4.67 and 1.77; 1.03-3.03) compared to those with euglycemia. Hypoglycemic neonates had an increased aOR for both death (2.85; 1.09-7.43) and NDI (2.50; 1.09-7.43), whereas hyperglycemic neonates had increased aOR of 2.52 (1.10-5.77) for death, but not NDI. CONCLUSIONS:Glycemic profile differs between neonates with moderate and severe HIE, and initial glycemic state is associated death or NDI at 22 to 36 months.