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To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P .001) than those without acute abnormalities.Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.ClinicalTrials.gov: NCT02811263.

BACKGROUND: To determine the prevalence and severity of acute kidney injury (AKI) at different time frames in relation to gestational age (GA) and birthweight (BW) in extremely low gestational age neonates (ELGAN). Our hypothesis is that ELGAN with lower GA and lower BW have higher AKI rates. METHODS: 923 ELGAN enrolled in the Preterm Erythropoietin Neuroprotection Trial were evaluated from birth until death or hospital discharge. AKI was defined according to kidney disease: improving global outcomes (KDIGO) definition from clinically-derived serum creatinine (SCr) measurements. Severe AKI was defined as stage 2 or higher. RESULTS: For the entire cohort, 351/923 (38.0%, CI = 34.8–41.3%) had at least one episode of stage 1 or higher AKI and 168/923 (18.2%, CI = 15.7–20.7%) had at least one episode of severe (stage 2 or higher) AKI. The prevalence of AKI stage 1 or higher for the entire cohort during the early (days 3–7), middle (days 8–14) and late follow-up period (after day 14) was 112/923 (12.1%, CI = 10.0–14.3%), 142/891 (15.9%, CI = 13.5–18.4%) and 249/875 (28.5%, CI = 25.4–31.5%), respectively. The rates of severe AKI during the hospital course were 27.8%, 21.9%, 13.6%, and 9.4% for the 24, 25, 26 and 27 week GA groups respectively. AKI rates were significantly higher with decreasing GA and decreasing BW for stated time trends (all p < 0.01 using tests for trend). CONCLUSIONS: AKI is relatively common in ELGAN during their initial hospital course, and is associated with lower GA and BW.

Objective Little data are available regarding erythropoietin (Epo) utilization patterns within neonatal intensive care units (NICUs). We sought to describe the trends in Epo utilization across a large cohort of U.S. NICUs.Study Design This is a retrospective cohort study of infants discharged from 2008 to 2017 using the Pediatrix Clinical Data Warehouse.Results We identified 704,159 eligible infants from 358 sites, of whom 9,749 (1.4%) had Epo exposure. For extremely low gestational age newborns (ELGANs), Epo exposure ranged from 7.6 to 13.5%. We found significant site variability in Epo utilization in ELGANs. Among the 299 NICUs caring for ELGANs during the study period, 184 (61.5%) never used Epo for this population, whereas 21 (7%) utilized Epo in 50% or more of eligible infants. Epo was initiated at a median of 25 days in ELGANs. For infants with hypoxic–ischemic encephalopathy (HIE), Epo exposure remained ≤1% through 2014 then increased fourfold to 3.4% by 2017. The median day of Epo initiation was the day of birth for infants diagnosed with HIE.Conclusion Epo is utilized in ELGANs more commonly than for other NICU populations. Utilization patterns appear to indicate the treatment of established anemia for ELGANs and more recently for neuroprotection in patients diagnosed with HIE.

OBJECTIVES To evaluate whether extremely preterm infants regulate iron status via hepcidin. STUDY DESIGN In this retrospective analysis of infants from the Preterm Epo Neuroprotection (PENUT) Trial, urine hepcidin (Uhep) normalized to creatinine (Uhep/UCr) was evaluated among infants randomized to erythropoietin (Epo) or placebo. RESULTS The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio [ZnPP/H]) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P

Objectives To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. Study design The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. Results One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. Conclusions Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial.This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision.In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status.Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

Introduction MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. Methods and analysis Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation—thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. Ethics and dissemination IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor. Trial registration number NCT02811263; Pre-result.

Challenges to obtaining consent for clinical research in acute settings are ubiquitous and yet highly specific to clinical context. Dickert and colleagues bring to light the challenges inherent in ...

The reticulocyte index reticulocyte hemoglobin equivalent (Ret-He) was evaluated as a marker of iron status. This is a retrospective cohort study of all infants admitted to the University of Washington Neonatal Intensive Care Unit, who received Ret-He measurements as part of routine care within the first 120 days of life. A total of 730 Ret-He measurements from 249 infants were analyzed (median gestational age at birth 32.1 weeks; 49 infants

Newborns with hypoxic–ischemic encephalopathy (HIE) may exhibit abnormalities on placental histology. In this phase II clinical trial ancillary study, we hypothesized that placental abnormalities correlate with MRI brain injury and with response to treatment. Fifty newborns with moderate/severe encephalopathy who received hypothermia were enrolled in a double-blind, placebo-controlled trial of erythropoietin for HIE. A study pathologist reviewed all available clinical pathology reports to determine the presence of chronic abnormalities and acute chorioamnionitis. Neonatal brain MRIs were scored using a validated HIE scoring system. Placental abnormalities in 19 of the 35 (54%) patients with available pathology reports included chronic changes (N = 13), acute chorioamnionitis (N = 9), or both (N = 3). MRI subcortical brain injury was less common in infants with a placental abnormality (26 vs. 69%, P = 0.02). Erythropoietin treatment was associated with a lower global brain injury score (median 2.0 vs. 11.5, P = 0.003) and lower rate of subcortical brain injury (33 vs. 90%, P = 0.01) among patients with no chronic placental abnormality but not in patients whose placentas harbored a chronic abnormality. Erythropoietin treatment was associated with less brain injury only in patients whose placentas exhibited no chronic histologic changes. Placentas may provide clues to treatment response in HIE.

Despite a high frequency of iron deficiency in pregnancy, the United States Preventative Services Task Force (USPSTF) stated: "there is inconclusive evidence routine supplementation for iron deficiency anemia improves maternal or infant clinical health outcomes." In contradistinction, high-quality epidemiologic studies report long lasting deficits in infants diagnosed with iron deficiency in the first 6 months of life compared with infants who were not, with specific deficits in cognition, memory, executive function and electrophysiology documented up to 19 years of age. Infants are not routinely screened for iron deficiency. United Kingdom guidelines differ and recommend screening high-risk infants who are preterm, of diabetic, underweight, obese, or vegetarian mothers, those born to anemic or iron deficient mothers, of smokers, those with inflammatory bowel disease or abnormal uterine bleeding, and from pregnancies in which the intergravid period is6 months. Iron parameters are not routinely drawn unless anemia is present and in some cases only if microcytic. In that iron deficiency precedes the development of anemia, and waiting for its development misses a large number of overtly iron deficient gravidas. Iron parameters were measured in 102 consecutive, nonselected, nonanemic, first trimester women presenting to their obstetricians. Using standard cutoffs of percent transferrin saturation and/or serum ferritin, 42% were observed to be iron deficient. Given the lack of harm of testing for iron deficiency, it appears prudent to err on the side of caution and screen all presenting pregnant mothers until properly powered outcome data become available. The current recommendations of the USPSTF may need to be revisited.

Data correlating dried blood spots (DBS) and plasma concentrations for neonatal biomarkers of brain injury are lacking. We hypothesized that candidate biomarker levels determined from DBS can serve as a reliable surrogate for plasma levels. In the context of a phase II multi-center trial evaluating erythropoietin for neuroprotection in neonatal encephalopathy (NE), DBS were collected at enrollment (

Iron deficiency, with or without anemia, is common in pregnant women. In fact, nearly 30% of reproductive-age women are anemic worldwide, and anemia in pregnancy has an estimated global prevalence of 38%. Severe anemia can substantially increase the risk of maternal mortality, and can adversely affect fetal development. In this review, we examine the available data regarding epidemiology and consequences of iron deficiency in mothers and infants, current treatment strategies, and make recommendations for screening and treatment of iron deficiency anemia in gravidas and neonates.

BACKGROUND AND OBJECTIVES: AKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by

Background: In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (

Extremely preterm infants are among the populations receiving the highest levels of transfusions. Erythropoietin has not been recommended for premature infants because most studies have not demonstrated a decrease in donor exposure.To determine whether high-dose erythropoietin given within 24 hours of birth through postmenstrual age of 32 completed weeks will decrease the need for blood transfusions.The Preterm Erythropoietin Neuroprotection Trial (PENUT) is a randomized, double-masked clinical trial with participants enrolled at 19 sites consisting of 30 neonatal intensive care units across the United States. Participants were born at a gestational age of 24 weeks (0-6 days) to 27 weeks (6-7 days). Exclusion criteria included conditions known to affect neurodevelopmental outcomes. Of 3266 patients screened, 2325 were excluded, and 941 were enrolled and randomized to erythropoietin (n = 477) or placebo (n = 464). Data were collected from December 12, 2013, to February 25, 2019, and analyzed from March 1 to June 15, 2019.In this post hoc analysis, erythropoietin, 1000 U/kg, or placebo was given every 48 hours for 6 doses, followed by 400 U/kg or sham injections 3 times a week through postmenstrual age of 32 weeks.Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein.A total of 936 patients (488 male [52.1%]) were included in the analysis, with a mean (SD) gestational age of 25.6 (1.2) weeks and mean (SD) birth weight of 799 (189) g. Erythropoietin treatment (vs placebo) decreased the number of transfusions (unadjusted mean [SD], 3.5 [4.0] vs 5.2 [4.4]), with a relative rate (RR) of 0.66 (95% CI, 0.59-0.75); the cumulative transfused volume (mean [SD], 47.6 [60.4] vs 76.3 [68.2] mL), with a mean difference of -25.7 (95% CI, 18.1-33.3) mL; and donor exposure (mean [SD], 1.6 [1.7] vs 2.4 [2.0]), with an RR of 0.67 (95% CI, 0.58-0.77). Despite fewer transfusions, erythropoietin-treated infants tended to have higher hematocrit levels than placebo-treated infants, most noticeable at gestational week 33 in infants with a gestational age of 27 weeks (mean [SD] hematocrit level in erythropoietin-treated vs placebo-treated cohorts, 36.9% [5.5%] vs 30.4% [4.6%] (P .001). Of 936 infants, 160 (17.1%) remained transfusion free at the end of 12 postnatal weeks, including 43 in the placebo group and 117 in the erythropoietin group (P .001).These findings suggest that high-dose erythropoietin as used in the PENUT protocol was effective in reducing transfusion needs in this population of extremely preterm infants.ClinicalTrials.gov Identifier: NCT01378273.

Background Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population. Methods This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions. Results Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group. Conclusions Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes. Impact Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.

Introduction: The Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial sought to determine the safety and efficacy of early high-dose Epo as a potential neuroprotective treatment. We hypothesized that Epo would not increase the incidence or severity of retinopathy of prematurity (ROP). Methods: A total of 941 infants born between 24–0/7 and 27–6/7 weeks’ gestation were randomized to 1,000 U/kg Epo or placebo intravenously for 6 doses, followed by subcutaneous or sham injections of 400 U/kg Epo 3 times a week through 32 weeks post-menstrual age. In this secondary analysis of PENUT trial data, survivors were evaluated for ROP. A modified intention-to-treat approach was used to compare treatment groups. In addition, risk factors for ROP were evaluated using regression methods that account for multiples and allow for adjustment for treatment and gestational age at birth. Results: Of 845 subjects who underwent ROP examination, 503 were diagnosed with ROP with similar incidence and severity between treatment groups. Gestational age at birth, birth weight, prenatal magnesium sulfate, maternal antibiotic exposure, and presence of heart murmur at 2 weeks predicted the development of any ROP, while being on high-frequency oscillator or high-frequency jet ventilation (HFOV/HFJV) at 2 weeks predicted severe ROP. Conclusion: Early high-dose Epo followed by maintenance dosing through 32 weeks does not increase the risk of any or severe ROP in extremely low gestational age neonates. Gestational age, birth weight, maternal treatment with magnesium sulfate, antibiotic use during pregnancy, and presence of a heart murmur at 2 weeks were associated with increased risk of any ROP. Treatment with HFOV/HFJV was associated with an increased risk of severe ROP.

OBJECTIVE: To evaluate whether extremely low gestational age neonates (ELGANs) randomized to erythropoietin have better or worse kidney-related outcomes during hospitalization and at 22–26 months corrected gestational age (cGA) compared with those randomized to placebo. STUDY DESIGN: We performed an ancillary study to a multicenter double-blind, placebo-controlled randomized clinical trial of erythropoietin in ELGANs. RESULTS: The prevalence of severe (stage 2 or 3) acute kidney injury (AKI) was 18.2%. We did not find a statistically significant difference between those randomized to erythropoietin vs. placebo for in-hospital primary (severe AKI) or secondary outcomes (any AKI and serum creatinine [SCr]/ cystatin C values at days 0, 7, 9 and 14). At 22–26 months cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) 30 mg/g, 23% had a systolic blood pressure (SBP) >95(th) percentile for age, and 40% had a diastolic blood pressure (DBP) >95(th) percentile for age. SBP >90(th) percentile occurred less often among recipients of erythropoietin (p95(th) percentile or DBP >90(th) or >95(th) percentiles. CONCLUSIONS: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22–26 months cGA. Recombinant erythropoietin (rhEpo) may protect ELGANs against long-term elevated SBP, but does not appear to protect from AKI, low eGFR, albuminuria or elevated DBP at 22–26 months cGA.

OBJECTIVES: (1) To identify a resource use inflection point (RU-IP) beyond which patients in the NICU no longer received NICU-level care, (2) to quantify variability between hospitals in patient-days beyond the RU-IP, and (3) to describe risk factors associated with reaching an RU-IP. METHODS: We evaluated infants admitted to any of the 43 NICUs over 6 years. We determined the day that each patient’s total daily standardized cost was RESULTS: Among 80 821 neonates, 80.6% reached an RU-IP. In total, there were 234 478 days after the RU-IP, representing 24.3% of the total NICU days and $483 281 268 in costs. Variability in the proportion of patients reaching an RU-IP was 33.1% to 98.7%. Extremely preterm and very preterm neonates, patients discharged with home health care services, or patients receiving mechanical ventilation, extracorporeal membrane oxygenation, or feeding support exhibited fewer days beyond the RU-IP. Conversely, receiving methadone was associated with increased days beyond the RU-IP. CONCLUSIONS: Identification of an RU-IP may allow health care systems to identify readiness for discharge from the NICU earlier and thereby save significant NICU days and health care dollars. These data reveal the need to identify best practices in NICUs that consistently discharge infants more efficiently. Once these best practices are known, they can be disseminated to offer guidance in creating quality improvement projects to provide safer and more predictable care across hospitals for patients of all socioeconomic statuses.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.)

Hypoxic ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. Our study sought to examine whether patterns of newborn screening analytes differed between infants with and without neonatal HIE in order to identify opportunities for potential use of these analytes for diagnosis in routine clinical practice. We linked a population-based newborn screening registry with health databases to identify cases of HIE among term infants (≥37 weeks’ gestation) in Ontario from 2010–2015. Correlations between HIE and screening analytes were examined using multivariable logistic regression models containing clinical factors and individual screening analytes (acyl-carnitines, amino acids, fetal-to-adult hemoglobin ratio, endocrine markers, and enzymes). Among 731,841 term infants, 3,010 were diagnosed with HIE during the neonatal period. Multivariable models indicated that clinical variables alone or in combination with hemoglobin values were not associated with HIE diagnosis. Although the model was improved after adding acyl-carnitines and amino acids, the ability of the model to identify infants with HIE was moderate. Our findings indicate that analytes associated with catabolic stress were altered in infants with HIE; however, future research is required to determine whether amino acid and acyl-carnitine profiles could hold clinical utility in the early diagnosis or clinical management of HIE. In particular, further research should examine whether cord blood analyses can be used to identify HIE within a clinically useful timeframe or to guide treatment and predict long-term health outcomes.

Brain injury around birth is associated with nearly half of all cases of cerebral palsy. Although brain injury is multifactorial, particularly after preterm birth, acute hypoxia-ischaemia is a major contributor to injury. It is now well established that the severity of injury after hypoxia-ischaemia is determined by a dynamic balance between injurious and protective processes. In addition, mothers who are at risk of premature delivery have high rates of diabetes and antepartum infection/inflammation and are almost universally given treatments such as antenatal glucocorticoids and magnesium sulphate to reduce the risk of death and complications after preterm birth. We review evidence that these common factors affect responses to fetal asphyxia, often in unexpected ways. For example, glucocorticoid exposure dramatically increases delayed cell loss after acute hypoxia-ischaemia, largely through secondary hyperglycaemia. This critical new information is important to understand the effects of clinical treatments of women whose fetuses are at risk of perinatal asphyxia.

There is a variability regarding timing of consent and personnel used in patient recruitment for neonatal research. We explored the associations between the study personnel and timing of consent with parents’ decisional conflict and ultimately their decision to enroll. This was a multi-site, cross-sectional survey conducted between August 2015 and October 2017. Participants were parents approached to enroll their 24–28-week infant in a clinical trial. Parents completed an interviewer-administered 61-item questionnaire. Overall, 163 surveys were completed; 105 by parents of enrolled infants and 58 by parents of non-enrolled infants (54.5% participation rate). Neither the individual requesting nor timing of consent was associated with parents’ knowledge score, decisional conflict, or decision to enroll. Parents preferred to be approached prenatally and by their infant’s doctor. Study designers and IRBs may allow flexibility in personnel and timing of consent as it is respectful of parents and may enhance trial enrollment.

Inflammation caused by perinatal infection, superimposed with hypoxia and/or hyperoxia, appears to be important in the pathogenesis of preterm neonatal encephalopathy, with white matter particularly vulnerable during the third trimester. The associated inflammatory response is at least partly mediated through Toll-like receptor (TLR)-dependent mechanisms. Immunohistochemistry, gene expression, and behavioral studies were used to characterize white matter development and determine TLR3 and TLR4 expression and accumulation in the neonatal ferret brain. Expression of markers of white matter development increased significantly between postnatal day (P)1 and P10 (NG2, PDGFRα) or P15 (Olig2), and either remained elevated (NG2), or decreased again at P40 (PDGFRα, Olig2). Olig2 immunostaining within the internal capsule was also greatest at P15. Myelin basic protein (MBP) immunostaining and mRNA expression increased markedly from P15 to P40 and into adulthood, which correlated with increasing performance on behavioral tests (negative geotaxis, cliff aversion, righting reflex, and catwalk gait analysis). TLR4 and TLR3 positive staining was low at all ages, but TLR3 and TLR4 mRNA expression both increased significantly from P1 to P40. Following lipopolysaccharide (LPS) and hypoxia/hyperoxia exposure at P10, meningeal and parenchymal inflammation was seen, including an increase in TLR4 positive cells. These data suggest that the neuroinflammation associated with prematurity could be modeled in the newborn ferret.

Objectives To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development, third edition (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). Study design This is a post hoc analysis of a randomized trial that enrolled infants born at 24-28 completed weeks of gestation. All infants in PENUT who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. Results In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7 mg/kg/d (IQR 2.1-5.8 mg/kg/d) at day 60, with a mean of 3.6 mg/kg/d in infants treated with placebo and 4.8 mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Greater iron doses were associated with greater motor and language scores but did not reach statistical significance. Results at 90 days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater. Conclusions A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in infants born preterm, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo. Trial registration Clinicaltrials.gov : NCT01378273 .

Objectives To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 240/7 to 276/7 weeks of gestational age and to characterize the association between ICH and death or neurodevelopmental impairment (NDI) at 2 years of corrected age. Study design Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial had serial cranial ultrasound scans performed on day 1, day 7-9, and 36 weeks of postmenstrual age to evaluate ICH. Potential risk factors for development of ICH were examined. Outcomes included death or severe NDI as well as Bayley Scales of Infant and Toddler Development, 3rd Edition, at 2 years of corrected age. Results ICH was identified in 38% (n = 339) of 883 enrolled infants. Multiple gestation and cesarean delivery reduced the risk of any ICH on day 1. Risk factors for development of bilateral Grade 2, Grade 3, or Grade 4 ICH at day 7-9 included any ICH at day 1; 2 or more doses of prenatal steroids decreased risk. Bilateral Grade 2, Grade 3, or Grade 4 ICH at 36 weeks were associated with previous ICH at day 7-9. Bilateral Grade 2, any Grade 3, and any Grade 4 ICH at 7-9 days or 36 weeks of postmenstrual age were associated with increased risk of death or severe NDI and lower Bayley Scales of Infant and Toddler Development, 3rd Edition, scores. Conclusions Risk factors for ICH varied by timing of bleed. Bilateral and increasing grade of ICH were associated with death or NDI in infants born extremely preterm.

We aimed to evaluate diffusion tensor imaging (DTI) in infants born extremely preterm, to determine the effect of erythropoietin (Epo) on DTI, and to correlate DTI with neurodevelopmental outcomes at 2 years of age for infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Infants who underwent MRI with DTI at 36 weeks postmenstrual age were included. Neurodevelopmental outcomes were evaluated by Bayley Scales of Infant and Toddler Development (BSID-III). Generalized linear models were used to assess the association between DTI parameters and treatment group, and then with neurodevelopmental outcomes. A total of 101 placebo- and 93 Epo-treated infants underwent MRI. DTI white matter mean diffusivity (MD) was lower in placebo- compared to Epo-treated infants in the cingulate and occipital regions, and occipital white matter fractional isotropy (FA) was lower in infants born at 24–25 weeks vs. 26–27 weeks. These values were not associated with lower BSID-III scores. Certain decreases in clustering coefficients tended to have lower BSID-III scores. Consistent with the PENUT Trial findings, there was no effect on long-term neurodevelopment in Epo-treated infants even in the presence of microstructural changes identified by DTI.

Key Points Question Is there an association between 2-year neurodevelopmental outcomes and use of opioids and/or benzodiazepines for sedation and analgesia in extremely preterm infants? Findings In this cohort study of 936 infants born at gestational ages between 24 weeks, 0 days, and 27 weeks, 6 days, those exposed to both opioids and benzodiazepines for more than 7 days were more likely to have increased in-hospital morbidities, prolonged length of stay, and lower BSID-III cognitive, motor, and language scores at 2 years’ corrected age compared with infants without exposure or those exposed to opioids or benzodiazepines alone. Meaning In this study, the use of opioids and/or benzodiazepines among extremely preterm infants was associated with adverse effects on 2-year neurodevelopmental outcomes., This cohort study describes the use of opioids and benzodiazepines in extremely preterm infants during neonatal intensive care unit hospitalization and explores these drugs’ association with neurodevelopmental outcomes at 2 years’ corrected age., Importance Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs’ association with neurodevelopmental outcomes is poorly understood. Objectives To describe the use of opioids and benzodiazepines in EP infants during neonatal intensive care unit (NICU) hospitalization and to explore these drugs’ association with neurodevelopmental outcomes at 2 years’ corrected age. Design, Setting, and Participants This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial, which was conducted among infants born between gestational ages of 24 weeks, 0 days, and 27 weeks, 6 days. Infants received care at 19 sites in the United States, and data were collected from December 2013 to September 2016. Data analysis for this study was conducted from March to December 2020. Exposures Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay. Main Outcomes and Measures Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development–Third Edition (BSID-III). Results There were 936 EP infants (448 [48%] female infants; 611 [65%] White infants; mean [SD] gestational age, 181 [8] days) included in the study, and 692 (74%) had neurodevelopmental outcome data available. Overall, 158 infants (17%) were not exposed to any drugs of interest, 297 (32%) received either opioids or benzodiazepines, and 481 (51%) received both. Infants exposed to both had adjusted odds ratios of 9.7 (95% CI, 2.9 to 32.2) for necrotizing enterocolitis and 1.7 (95% CI, 1.1 to 2.7) for severe bronchopulmonary dysplasia; they also had a longer estimated adjusted mean difference in length of stay of 34.2 (95% CI, 26.2 to 42.2) days compared with those who received neither drug. After adjusting for site and propensity scores derived for each exposure category, infants exposed to opioids and benzodiazepines had lower BSID-III cognitive, motor, and language scores compared with infants with no exposure (eg, estimated difference in mean scores on cognitive scale: −5.72; 95% CI, –8.88 to –2.57). Prolonged exposure to morphine, fentanyl, midazolam, or lorazepam was associated with lower BSID-III scores compared with infants without exposure (median [interquartile range] motor score, 85 [73-97] vs 97 [91-107]). In contrast, BSID-III scores for infants with short exposure to both opioids and benzodiazepines were not different than those of infants without exposure. Conclusions and Relevance In this study, prolonged combined use of opioids and benzodiazepines was associated with a risk of poorer neurodevelopmental outcomes as measured by BSID-III at 2 years’ corrected age.

Background Iron deficiency during critical windows of brain development is associated with suboptimal neurodevelopmental outcomes. Identifying markers of neonatal iron status that best correlate with neurodevelopmental outcome is critical for optimal management of iron supplementation of neonates. Aims We aimed to evaluate two markers of iron sufficiency, ferritin and zinc protoporphyrin-to-heme ratios (ZnPP/H), with neurodevelopmental outcomes. Study design This is a retrospective cohort study. Subjects All infants with concurrent ferritin and ZnPP/H measurements obtained between October 2014 and April 2017 and Bayley Scales of Infant Development, 3rd Edition (BSID-III) evaluated at 24 months corrected age were included. Outcome measures Associations between iron markers (minimum, maximum and median ferritin and ZnPP/H) and BSID-III score at 24 months were assessed. Results 223 lab measurements from 62 infants were assessed. Mean gestational age was 28.1 weeks (SD = 2.6) with a mean birth weight of 1.1 kg (SD = 0.4). Significant associations between maximum and median ZnPP/H and motor score, and between median ZnPP/H and cognitive score were observed. Trends were also seen with higher minimum, median and maximum ZnPP/H associated with lower BSID-III scores, but did not reach statistical significance (p > 0.05). The associations between ferritin values and BSID scores were less consistent. Conclusions A positive association was seen between ZnPP/H values and BSID-III scores. Trends between ferritin and BSID values were less consistent, potentially because ferritin is more affected by inflammation. Consideration should be given to using ZnPP/H preferentially to adjust iron supplementation in the NICU to improve neurodevelopmental outcomes.

In neonates, the validation of urinary biomarkers to diagnose acute kidney injury is a rapidly evolving field. The neonatal population poses unique challenges when assessing the collection, storage, and processing of urinary samples for biomarker analysis. Given this, establishing optimal and consistent sample processing in this population for meaningful use in ongoing clinical trials is important. Urine from a cohort of 19 hospitalized neonatal intensive care unit patients enrolled in the Preterm Erythropoietin Neuroprotection Trial (Clinical Trial NCT01378273) was collected for biomarker analysis by indirect techniques using Fisher-brand cotton balls placed in the diapers. Fourteen urinary biomarkers were measured using commercially available kits via electrochemiluminescence on multiarray plates and compared between paired samples processed with centrifugation prior to storage versus prior to analysis. None of the biomarker concentrations differed between samples undergoing centrifugation prior to storage versus prior to analysis. The difference between samples was within 2% of the estimated concentration for the protein in 12 of 14 biomarkers (86%), and all paired biomarker concentrations were within 4%. The percentage error analysis did not show a difference between paired samples, with biomarker percentage errors smaller than the stated immunoassay coefficient of variance. The urinary concentrations of biomarkers were comparable between paired samples, demonstrating that indirectly collected neonatal urine samples do not require centrifugation after collection and before storage. The ability to use routine urine collection and storage methods to obtain samples for subsequent quantitative immunoassay analysis should facilitate studies of newborns and young children.

Background: Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited. Methodology: Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed. Results: All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP. Conclusions/Significance: In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.

Advances in neonatology have led to unprecedented improvements in neonatal survival such that those born as early as 22 weeks of gestation now have some chance of survival, and over 70% of those born at 24 weeks of gestation survive. Up to 50% of infants born extremely preterm develop poor outcomes involving long-term neurodevelopmental impairments affecting cognition and learning, or motor problems such as cerebral palsy. Poor outcomes arise because the preterm brain is vulnerable both to direct injury (by events such as intracerebral hemorrhage, infection, and/or hypoxia), or indirect injury due to disruption of normal development. This neonatal brain injury and/or dysmaturation is called "encephalopathy of prematurity". Current and future strategies to improve outcomes in this population include prevention of preterm birth, and pre-, peri-, and postnatal approaches to protect the developing brain. This review will describe mechanisms of preterm brain injury, and current and upcoming therapies in the antepartum and postnatal period to improve preterm encephalopathy.

Bronchopulmonary dysplasia (BPD) remains a devastating consequence of prematurity. Repeated inflammatory insults worsen lung injury, but there are no predictors for BPD-related respiratory outcomes or targeted therapies. We sought to understand inflammatory mechanisms in evolving BPD through molecular characterization of monocytes in tracheal aspirates from infants at risk for developing BPD. We performed flow cytometry targeting myeloid cell populations on prospectively collected tracheal aspirates from intubated patients born before 29 wk of gestation and +CD16+ (double-positive) and CD14+CD16− (single-positive) monocytes and characterized their gene expression profiles by RNA sequencing and quantitative PCR. We further analyzed differential gene expression between time points to evaluate changes in monocyte function over the first weeks of life. Expression of IL-1A, IL-1B, and IL-1 receptor antagonist mRNA was increased in monocytes collected at day of life ( DOL) 7, DOL 14, and DOL 28 compared with those collected at DOL 3. This study suggests that early changes in monocyte-specific IL-1 cytokine pathways may be associated with evolving BPD.

OBJECTIVE: Characterize frequency and volume of blood draws and transfusions in extremely low birth weight infants in the first 10 weeks of life. STUDY DESIGN: We included infants with a birth weight

Neonatal encephalopathy (NE) is a major cause of neonatal mortality and morbidity. Therapeutic hypothermia (TH) is standard treatment for newborns at 36 weeks of gestation or greater with intrapartum hypoxia-related NE. Term and late preterm infants with moderate to severe encephalopathy show improved survival and neurodevelopmental outcomes at 18 months of age after TH. TH can increase survival without increasing major disability, rates of an IQ less than 70, or cerebral palsy. Neonates with severe NE remain at risk of death or severe neurodevelopmental impairment. This review discusses the evidence supporting TH for term or near term neonates with NE.

Intraventricular hemorrhage (IVH) is a common and potentially devastating adverse outcome affecting up to 30% of preterm infants. β-Lactam antibiotics affect platelet activation through interaction with platelet surface receptors. The objective of this study was to evaluate an association between ampicillin use and the development of IVH in preterm infants. This was a single-center and a retrospective case-control study of preterm low-birth-weight infants diagnosed with IVH and matched controls without IVH. Conditional logistic regression was performed on 10 clinical features from the first week of life to evaluate the association with IVH. Data were obtained for 174 subjects with no significant differences between groups in demographic factors and level of illness indicators. Earlier administration of the first dose of ampicillin was associated with increased odds of developing IVH (odds ratio [OR]: 0.95, p = 0.028) when controlling for other common associations. Longer courses of ampicillin were not significantly associated with the development of IVH (OR: 1.13, p = 0.089). The odds of developing IVH in our population increased with earlier, but not longer initial courses of ampicillin. Further research into the associations with IVH should include the assessment of ampicillin dose, timing, and duration.

Altered cerebral perfusion from impaired autoregulation may contribute to the morbidity and mortality associated with premature birth. We hypothesized that fast Doppler imaging could provide a reproducible bedside estimation of cerebral perfusion and autoregulation in preterm infants. This is a prospective pilot study using fast Doppler ultrasound to assess blood flow velocity in the basal ganglia of 19 subjects born at 26–32 wk gestation. Intraclass correlation provided a measure of test–retest reliability, and linear regression of cerebral blood flow velocity and heart rate or blood pressure allowed for estimations of autoregulatory ability. The intraclass correlation when imaging in the first 48 h of life was 0.634. We found significant and independent correlations between the systolic blood flow velocity and both systolic blood pressure and heart rate (P = 0.015 and 0.012 respectively) only in the 26–28 wk gestational age infants in the first 48 h of life. Our results suggest that fast Doppler provides reliable bedside measurements of cerebral blood flow velocity at the tissue level in premature infants, acting as a proxy for cerebral tissue perfusion. Additionally, autoregulation appears to be impaired in the extremely preterm infants, even within a normal range of blood pressures.

Background: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection. Objectives: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. Methods: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. Results and Conclusions: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

To evaluate ferritin and zinc protoporphyrin-to-heme (ZnPP/H) ratios as biomarkers of iron status in neonates, determine how specific clinical events affected these measures, and assess how iron status changed during hospitalization.We performed a retrospective study of all infants with paired ferritin and ZnPP/H measurements between October 2014 and May 2016. Concordance of these measurements, effects of sepsis, red blood cell transfusion, erythropoietin treatment, and iron supplementation were assessed. Iron status was measured over time.A total of 228 patients (mean birth weight 1.3 kg, median gestational age 29 weeks) were evaluated. Mean log ZnPP/H values in infants with and without sepsis were not significantly different (4.98 µmol/mol vs 4.97 µmol/mol, adjusted P = .103), whereas log-transformed ferritin values increased significantly during infection (5.23 ng/mL vs 4.04 ng/mL, adjusted P .001). Ferritin also increased more significantly than ZnPP/H following red blood cell transfusion (ferritin: mean 5.03 ng/mL vs 4.0 ng/mL, P .001; ZnPP/H: mean 4.85 µmol/mol vs 4.98 µmol/mol, P .001). The mean iron supplementations at 30, 60, and 90 days were 5.4, 6.9, and 7.4 mg/kg/day, respectively. Ferritin values decreased with advancing postnatal age (adjusted P .001), with 66% of ferritin values less than 76 ng/mL. Treatment with erythropoietin increased ZnPP/H, but not ferritin levels.Ferritin is more significantly affected by inflammatory events such as sepsis and transfusion than ZnPP/H, thus, ZnPP/H may be a more reliable marker of iron status in this population. Infants showed worsening iron sufficiency over time despite supplementation above American Academy of Pediatrics guidelines.

Traumatic brain injury (TBI) is a leading cause of acquired neurologic disability in children. Erythropoietin (EPO), an anti-apoptotic cytokine, improved cognitive outcome in adult rats after TBI. To our knowledge, EPO has not been studied in a developmental TBI model. Hypothesis: We hypothesized that EPO would improve cognitive outcome and increase neuron fraction in the hippocampus in 17-day-old (P17) rat pups after controlled cortical impact (CCI). Methods: EPO or vehicle was given at 1, 24, and 48 h after CCI and at post injury day (PID) 7. Cognitive outcome at PID14 was assessed using Novel Object Recognition (NOR). Hippocampal EPO levels, caspase activity, and mRNA levels of the apoptosis factors Bcl2, Bax, Bcl-xL, and Bad were measured during the first 14 days after injury. Neuron fraction and caspase activation in CA1, CA3, and DG were studied at PID2. Results: EPO normalized recognition memory after CCI. EPO blunted the increased hippocampal caspase activity induced by CCI at PID1, but not at PID2. EPO increased neuron fraction in CA3 at PID2. Brain levels of exogenous EPO appeared low relative to endogenous. Timing of EPO administration was associated with temporal changes in hippocampal mRNA levels of EPO and pro-apoptotic factors. Conclusion/Speculation: EPO improved recognition memory, increased regional hippocampal neuron fraction, and decreased caspase activity in P17 rats after CCI. We speculate that EPO improved cognitive outcome in rat pups after CCI as a result of improved neuronal survival via inhibition of caspase-dependent apoptosis early after injury.

Background Cerebellar hypoplasia is common problem for preterm infants, and infants that suffer intraventricular hemorrhage (IVH). To evaluate the effects of IVH on cerebellar growth and development, we used a neonatal rabbit model of systemic glycerol to produce IVH. Methods New Zealand White rabbit kits were surgically delivered 2 d preterm, and treated with i.p. glycerol (3.25 to 6.5 g/kg). Controls were born at term. IVH was documented by ultrasound. Brain MRI volumes, cerebellar foliation, proliferation (Ki-67) and Purkinje cell density were done at two weeks of life. Tissue glycerol and glutathione concentrations were measured. Results Glycerol increased IVH, subarachnoid hemorrhages and mortality in a dose-dependent manner. Total cerebellar volumes, cerebellar foliation and cerebellar proliferation were decreased in a dose-dependent manner. Glycerol accumulated rapidly in blood, brain and liver and was associated with increased glutathione concentration. All of these results were independent of IVH status. Conclusions Cerebellar hypoplasia was induced after glycerol administration in a dose-dependent manner. Given rapid tissue accumulation of glycerol, dose dependent decreased brain growth and lack of IVH effect on measured outcomes we question the validity of this model as glycerol toxicity cannot be ruled out. A more physiologic model of IVH is needed.

Studies published 27 years ago showed that erythroid progenitor cells of preterm neonates were responsive to recombinant erythropoietin (Epo).1 Many clinical trials were subsequently performed worldwide, testing whether administering Epo to preterm infants might be a safe and effective way to expand their red cell mass and decrease their transfusion requirements. Indeed, essentially all trials convincingly showed that Epo can stimulate erythropoiesis in preterm and term infants, and has the capability to diminish donor exposure and decrease transfusions. Recent randomized, multi-centered, placebo-controlled trials of erythropoiesis stimulating agents (ESAs), such as Epo or longer acting darbepoetin, administered to preterm infants also show a reduction in blood donor exposure and a lower transfusion rate.2 Along with the clinical trials aimed at decreasing or eliminating transfusions, animal studies have shown that ESAs have neuroprotective effects, thought to be in part the result of ESA’s inhibition of apoptosis. These encouraging findings paved the way for clinical trials that are currently underway, evaluating clinically relevant neurodevelopment effects of ESAs in high-risk neonatal populations. Higher doses of ESAs than those used in stimulating erythropoiesis have been proposed to achieve Epo concentrations capable of crossing the blood brain barrier to produce therapeutic levels in the brain. Doses from 1000 to 3000 units/kg have been evaluated in pilot studies of preterm infants3,4 and in term neonates receiving therapeutic hypothermia for hypoxic ischemic encephalopathy.5 Darbepoetin has been evaluated in term neonates with hypoxic ischemic encephalopathy being cooled,6 and in preterm infants to improve neurocognitive outcomes,7 with encouraging neurodevelopmental results. Although the most effective neuroprotective dose and dosing intervals of these ESAs have yet to be determined, evidence is accumulating that ESAs have favorable neuroprotective effects in both preterm7,8 and term infants.9 In this issue of The Journal, Fauchere et al report hospital outcomes of a randomized clinical trial testing high dose Epo in preterm infants.10 Although results of the primary outcome of the study—neurodevelopment at 24 months—are pending, a subset of infants enrolled in the study had magnetic resonance imaging at term-corrected age, which showed that the infants treated with Epo had lower white and grey matter injury scores.11 In the current study, over 450 infants were randomized in masked fashion to receive placebo (NaCl 0.9%) or intravenous Epo, 3000 units/kg administered at 3, 12–18, and 36–42 hours after birth. This initial report focused on the safety of early high dose Epo, and followed the hospital course of all enrollees. No safety issues were identified. Specifically, there were no differences in the occurrence of any intracranial hemorrhage (11.4% in the Epo-treated group vs 9.6% in the placebo group) or of retinopathy of prematurity (ROP). The overall incidence of any stage ROP in the Epo treated group was 9.5% (1.9% for ROP ≥stage 3), vs 10.2% (3.7% for ROP ≥stage 3) in the placebo group. The safety data are reassuring both to Epo investigators evaluating potential neuroprotective effects, and to clinicians currently using Epo to avoid transfusions in preterm infants.10 Although early studies of Epo administered to preterm infants were promising, meta-analyses published in 200612,13 reversed the trend of Epo use in many neonatal intensive care units. The authors of the 2006 reviews separated Epo studies into early (first week of life) and late (after the first week) administration, and concluded that the incidence of ≥stage 3 ROP was increased with early Epo administration. Only 1 study in this meta-analysis reported an increase in ROP among recipients of Epo, a single-center study by Romagnoli et al.14 In revised meta-analyses15,16 of the 27 studies randomizing 2209 infants to early Epo or placebo, the incidence of ROP was reported in 7 studies, comprising only 36% of all study infants. Despite their initial report in 2000, Romagnoli et al continued to study Epo,17 and Epo is currently standard of care in their unit.17 Currently, ample evidence exists that administering ESAs to selected neonatal populations significantly diminishes transfusion requirements and blood donor exposures, reduces transfusion costs, and conserves blood bank resources.18,19 In addition, there is mounting evidence—bolstered by recent studies including this study by Fauchere et al—indicating that early Epo administration to preterm neonates does not increase their risk for developing ROP or any other complications of prematurity. We eagerly await the long-term follow-up results of this and other studies such as the Preterm Erythropoietin for Neuroprotection (PE-NUT) study to determine whether high dose ESAs are also neuroprotective.

We describe the development of fetal brain lesions after Zika virus (ZIKV) inoculation in a pregnant pigtail macaque. Periventricular lesions developed within 10 d and evolved asymmetrically in the occipital-parietal lobes. Fetal autopsy revealed ZIKV in the brain and significant cerebral white matter hypoplasia, periventricular white matter gliosis, and axonal and ependymal injury. Our observation of ZIKV-associated fetal brain lesions in a nonhuman primate provides a model for therapeutic evaluation.

Perinatal brain injury frequently complicates preterm birth and leads to significant long-term morbidity. Cytokines and inflammatory cells are mediators in the common pathways associated with perinatal brain injury induced by a variety of insults, such as hypoxic-ischemic injury, reperfusion injury, toxin-mediated injury, and infection. This paper examines our current knowledge regarding cytokine-related perinatal brain injury and specifically discusses strategies for attenuating cytokine-mediated brain damage.

Cerebral palsy (CP) is the most common cause of severe physical disability in childhood, occurring in approximately 2 in 1,000 liveborn infants. Although the prevalence of CP appears to have stabilized in the past 2 decades, recent studies suggest that severe CP may be decreasing. Neuroimaging studies help identify abnormal neuroanatomic findings, which are found in most affected children. Neuropathology identified by magnetic resonance imaging (MRI) corresponds well to clinical descriptions of motor impairment in children who have CP. Clinical risk factors, combined with imaging studies, can help identify a subpopulation of infants who are at high risk for poor neurodevelopmental outcome. Counseling caregivers on future adverse developmental risks can be challenging for the clinician in the neonatal intensive care unit (NICU), especially because the cause of CP remains unexplained in most cases and is typically diagnosed outside the neonatal period. Early counseling of families of at-risk neonates may function as the starting point for parental adaptation to a lifelong condition that requires ongoing services and adjustments to promote the overall health and well-being of their child.