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The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD).A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization.Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD.We find no support for an increased risk of BPD with iron supplementation.NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

Background In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. Methods Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4–6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. Results Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5–5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. Conclusion In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. Impact Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

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.

To determine whether an intraventricular hemorrhage (IVH) prevention bundle featuring midline-elevated positioning reduced IVH among high-risk infants.In a retrospective study design, we compared outcomes of infants1250 grams birth weight or30 weeks gestation before (N = 205) and after (N = 360) implementation of an IVH prevention bundle, using Bayesian and frequentist logistic regression to determine whether the intervention decreased any grade IVH.In both the Bayesian and frequentist analyses, there was no difference in odds of any grade IVH before and after the implementation of the prevention bundle (OR 0.993; 95% Credible Interval 0.751-1.323 and OR 1.23; 95% Confidence Interval 0.818-1.864 respectively). Bias analyses suggested that these results were robust to bias from potential deaths attributable to IVH.In this retrospective analysis, we found no evidence for a protective effect of an IVH prevention bundle on IVH incidence among high-risk neonates at a level IV NICU.

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.

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.

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.

BACKGROUND Our understanding of the normative concentrations of urine biomarkers in premature neonates is limited. METHODS We evaluated urine from 750 extremely low gestational age (GA) neonates without severe acute kidney injury (AKI) to determine how GA affects ten different urine biomarkers at birth and over the first 30 postnatal days. Then, we investigated if the urine biomarkers changed over time at 27, 30, and 34 weeks postmenstrual age (PMA). Next, we evaluated the impact of sex on urine biomarker concentrations at birth and over time. Finally, we evaluated if urine biomarkers were impacted by treatment with erythropoietin (Epo). RESULTS We found that all ten biomarker concentrations differ at birth by GA and that some urine biomarker concentrations increase, while others decrease over time. At 27 weeks PMA, 7/10 urine biomarkers differed by GA. By 30 weeks PMA, 5/10 differed, and by 34 weeks PMA, only osteopontin differed by GA. About half of the biomarker concentrations differed by sex, and 4/10 showed different rates of change over time between males vs. females. We found no differences in urine biomarkers by treatment group. CONCLUSIONS The temporal patterns, GA, and sex differences need to be considered in urine AKI biomarker analyses. IMPACT Urine biomarker concentrations differ by GA at birth. Some urine biomarkers increase, while others decrease, over the first 30 postnatal days. Most urine biomarkers differ by GA at 27 weeks PMA, but are similar by 34 weeks PMA. Some urine biomarkers vary by sex in premature neonates. Urine biomarkers did not differ between neonates randomized to placebo vs. Epo.

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.

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.

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.

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 High-dose erythropoietin (Epo) is a promising neuroprotective treatment in neonates with hypoxic ischemic encephalopathy (HIE) receiving hypothermia. We evaluated the pharmacokinetics and dose-exposure relationships of high-dose Epo in this population to inform future dosing strategies. Methods We performed a population pharmacokinetic analysis of 47 neonates with HIE treated with hypothermia who received up to 6 doses of Epo in two previous clinical trials. We compared the ability of different dosing regimens to achieve the target neuroprotective Epo exposure levels determined from animal models of hypoxic-ischemia (i.e., area under the curve during the first 48 hours of treatment [AUC48h] 140,000 mU*h/ml). Results Birth weight scaled via allometry was a significant predictor of Epo clearance and volume of distribution (p

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.

There is growing evidence that long-chain polyunsaturated fatty acids (LCPUFAs) are of importance for normal brain development. Adequate supply of LCPUFAs may be particularly important for preterm infants, because the third trimester is an important period of brain growth and accumulation of arachidonic acid (n-6 LCPUFA) and docosahexaenoic acid (n-3 LCPUFA). Fatty acids from the n-6 and n-3 series, particularly, have important functions in the brain as well as in the immune system, and their absolute and relative intakes may alter both the risk of impaired neurodevelopment and response to injury. This narrative review focuses on the potential importance of the n-6:n-3 fatty acid ratio in preterm brain development. Randomized trials of post-natal LCPUFA supplementation in preterm infants are presented. Pre-clinical evidence, results from observational studies in preterm infants as well as studies in term infants and evidence related to maternal diet during pregnancy, focusing on the n-6:n-3 fatty acid ratio, are also summarized. Two randomized trials in preterm infants have compared different ratios of arachidonic acid and docosahexaenoic acid intakes. Most of the other studies in preterm infants have compared formula supplemented with arachidonic acid and docosahexaenoic acid to un-supplemented formula. No trial has had a comprehensive approach to differences in total intake of both n-6 and n-3 fatty acids during a longer period of neurodevelopment. The results from preclinical and clinical studies indicate that intake of LCPUFAs during pregnancy and post-natal development is of importance for neurodevelopment and neuroprotection in preterm infants, but the interplay between fatty acids and their metabolites is complex. The best clinical approach to LCPUFA supplementation and n-6 to n-3 fatty acid ratio is still far from evident, and requires in-depth future studies that investigate specific fatty acid supplementation in the context of other fatty acids in the diet.

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.

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.

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.

Certain groups of neonates are at high risk of developing long-term neurodevelopmental impairment (NDI) and might be considered candidates for neuroprotective interventions. This chapter will explore some of these high-risk groups, relevant mechanisms of brain injury, and specific mechanisms of cellular injury and death. The potential of erythropoietin (Epo) to act as a neuroprotective agent for neonatal brain injury will be discussed. Clinical trials of Epo neuroprotection in preterm and term infants are updated.

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.

In the Neonatal Erythropoietin and Therapeutic Hypothermia Outcomes study, 9/20 erythropoietin-treated vs 12/24 placebo-treated infants with hypoxic-ischemic encephalopathy had acute brain injury. Among infants with acute brain injury, the injury volume was lower in the erythropoietin than the placebo group (P = .004). Higher injury volume correlated with lower 12-month neurodevelopmental scores. Trial registration ClinicalTrials.gov : NCT01913340 .

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.

OBJECTIVE: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy. METHODS: In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar RESULTS: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05). CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

The fetal-to-neonatal transition is one of the most complex processes in biological existence; much is unknown about this transition on the molecular and biochemical level. Based on growing metabolomics literature, we hypothesize that metabolomic analysis will reveal the key biochemical intermediates that change during the birth transition. Using two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC × GC–TOFMS), we identified 100 metabolites that changed during this transition. Of these 100 metabolites, 23 demonstrated significant change during the first 72 h. Of note, four intermediates of the tricarboxylic acid (TCA) cycle were identified (α-ketoglutaric acid, fumaric acid, malic acid, and succinyl-CoA), demonstrating a consistent rate of rise during the study. This may signify the transition of the neonate from a hypoxic in utero environment to an oxygen-rich environment. Important signaling molecules were also identified, including myo-inositol and glutamic acid. GC × GC–TOFMS was able to identify important metabolites associated with metabolism and signaling. These data can be used as a baseline for normal birth transition, which may aid in future perinatal research investigations. Late-preterm Macaca nemestrina were delivered by hysterotomy, with plasma drawn from the cord blood and after birth at eight additional time points to 72 h of age.

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.

Critically ill preterm infants experience multiple stressors while hospitalized. Morphine is commonly prescribed to ameliorate their pain and stress. We hypothesized that neonatal stress will have a dose-dependent effect on hippocampal gene expression, and these effects will be altered by morphine treatment. Male C57BL/6 mice were exposed to five treatment conditions between postnatal d 5 and 9: 1) control, 2) mild stress + saline, 3) mild stress + morphine, 4) severe stress + saline, and 5) severe stress + morphine. Hippocampal RNA was extracted and analyzed using Affymetrix Mouse Gene 1.0 ST Arrays. Single gene analysis and gene set analysis were used to compare groups with validation by qPCR. Stress resulted in enrichment of gene sets related to fear response, oxygen carrying capacity, and NMDA receptor synthesis. Morphine down-regulated gene sets related to immune function. Stress + morphine resulted in enrichment of mitochondrial electron transport gene sets and down-regulation of gene sets related to brain development and growth. We conclude that neonatal stress alone influences hippocampal gene expression, and morphine alters a subset of stress-related changes in gene expression and influences other gene sets. Stress + morphine show interaction effects not present with either stimulus alone. These changes may alter neurodevelopment.

Iron is essential for growth and development, and deficiency during gestation and infancy may have lifelong effects. Iron is necessary for oxygen transport, cellular respiration, myelination, neurotransmitter production, and cell proliferation. Iron deficiency may decrease hippocampal growth and alter oxidative metabolism, neurotransmitter concentrations, and fatty acid and myelination profiles throughout the brain. Excellent articles and reviews have been published on the effect of iron on cognitive development. This review highlights more recent findings, focusing on the role of iron in brain development during gestation and early life, and discusses implications for practice in the neonatal intensive care unit.

Purpose of review—Perinatal asphyxia, intraventricular hemorrhage and stroke are common causes of neonatal brain injury, with hypoxia-ischemia as the final common pathway of injury. Erythropoietin (Epo) has potential to lessen neurologic sequelae due to hypoxia-ischemia. The purpose of this review is to highlight new clinical trials and experimental evidence that expand our understanding of Epo as a potential treatment for perinatal brain injury. Recent findings—Several trials of Epo treatment are reviewed: Two phase I/II trials of high-dose Epo given to preterm infants established pharmacokinetic and safety profiles, and a trial of Epo treatment for term infants with moderate hypoxic-ischemic encephalopathy found reduced disability. Potential risks and benefits of high-dose Epo are discussed. New evidence related to Epo receptor expression, signal transduction pathways, and mechanisms of neuroprotection are reviewed. Summary—Cautious optimism is warranted regarding the use of high-dose Epo as a treatment option for neonatal brain injury. To date, Epo has been safe to use in neonatal populations and now studies of neuroprotective efficacy are underway.