Publications by authors named "Sandra Juul"

135 Publications

Gestational age, sex, and time affect urine biomarker concentrations in extremely low gestational age neonates.

Pediatr Res 2021 Nov 30. Epub 2021 Nov 30.

Department of Pediatrics, Cincinnati Children's Hospital Medical Center/University of Cincinnati College of Medicine, Cincinnati, OH, USA.

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.
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http://dx.doi.org/10.1038/s41390-021-01814-xDOI Listing
November 2021

Iron and Neurodevelopment in Preterm Infants: A Narrative Review.

Nutrients 2021 Oct 23;13(11). Epub 2021 Oct 23.

Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

Iron is critical for brain development, playing key roles in synaptogenesis, myelination, energy metabolism and neurotransmitter production. NICU infants are at particular risk for iron deficiency due to high iron needs, preterm birth, disruptions in maternal or placental health and phlebotomy. If deficiency occurs during critical periods of brain development, this may lead to permanent alterations in brain structure and function which is not reversible despite later supplementation. Children with perinatal iron deficiency have been shown to have delayed nerve conduction speeds, disrupted sleep patterns, impaired recognition memory, motor deficits and lower global developmental scores which may be present as early as in the neonatal period and persist into adulthood. Based on this, ensuring brain iron sufficiency during the neonatal period is critical to optimizing neurodevelopmental outcomes and iron supplementation should be targeted to iron measures that correlate with improved outcomes.
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http://dx.doi.org/10.3390/nu13113737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624708PMC
October 2021

Factors Associated with Outpatient Therapy Utilization in Extremely Preterm Infants.

Am J Perinatol 2021 Nov 9. Epub 2021 Nov 9.

Pediatrix Medical Group of San Antonio, San Antonio, United States.

Objective Factors influencing utilization of outpatient interventional therapies for extremely low gestational age newborns (ELGANs) after discharge remain poorly characterized, despite significant risk of neurodevelopmental impairment. We sought to assess the effects of maternal, infant, and environmental characteristics on outpatient therapy utilization in the first two years after discharge using data from the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Study Design This is a secondary analysis of 818 24-27 weeks' gestation infants enrolled in the PENUT trial who survived through discharge and completed at least one follow-up call or in-person visit between 4 and 24 months of age. Utilization of a state early intervention program (EI), physical (PT), occupational (OT), and speech (ST) therapies was recorded. Odds ratios and cumulative frequency curves for resource utilization were calculated for patient characteristics adjusting for gestational age, treatment group, and birth weight. Results 37% of infants did not access EI and 18% did not use any service (PT/OT/ST/EI). Infants diagnosed with severe morbidities (IVH, ROP, BPD, NEC), discharged with home oxygen, or with gastrostomy placement experienced increased utilization of PT, OT and ST compared to peers. However, substantial variation in service utilization occurred by state of enrollment and selected maternal characteristics. Conclusions ELGANs with severe medical comorbidities are more likely to utilize services after discharge. Therapy utilization may be impacted by maternal characteristics and state of enrollment. Outpatient therapy services remain significantly underutilized in this high-risk cohort. Further research is required to characterize and optimize utilization of therapy services following NICU discharge of ELGANs.
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http://dx.doi.org/10.1055/a-1692-0544DOI Listing
November 2021

Diffusion Tensor Imaging Changes Do Not Affect Long-Term Neurodevelopment following Early Erythropoietin among Extremely Preterm Infants in the Preterm Erythropoietin Neuroprotection Trial.

Brain Sci 2021 Oct 16;11(10). Epub 2021 Oct 16.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

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.
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http://dx.doi.org/10.3390/brainsci11101360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533828PMC
October 2021

Do Extremely Low Gestational Age Neonates Regulate Iron Absorption via Hepcidin?

J Pediatr 2021 Oct 7. Epub 2021 Oct 7.

Department of Pediatrics, University of Washington, Seattle, WA.

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 24-27 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 < .001). A significant association was seen between Uhep/UCr and ferritin at 2 weeks (r = 0.63; P < .001) and at 4 weeks (r = 0.41; P = .01) and between Uhep/UCr and ZnPP/H at 2 weeks (r = -0.49; P = .002).

Conclusions: Uhep/UCr values correlate with serum iron markers. Uhep/UCr values vary over time and are affected by treatment with Epo, suggesting that extremely preterm neonates can regulate hepcidin and therefore their iron status. Uhep is suppressed in extremely preterm neonates, particularly those treated with Epo.
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http://dx.doi.org/10.1016/j.jpeds.2021.09.059DOI Listing
October 2021

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial.

EBioMedicine 2021 Oct 4;72:103605. Epub 2021 Oct 4.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA. Electronic address:

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 (<28 weeks' gestation) infants.

Methods: Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III).

Findings: Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years.

Interpretation: Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice.

Funding: PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).
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http://dx.doi.org/10.1016/j.ebiom.2021.103605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498235PMC
October 2021

Evaluating Neuroprotective Effects of Uridine, Erythropoietin, and Therapeutic Hypothermia in a Ferret Model of Inflammation-Sensitized Hypoxic-Ischemic Encephalopathy.

Int J Mol Sci 2021 Sep 11;22(18). Epub 2021 Sep 11.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.

Perinatal hypoxic-ischemic (HI) brain injury, often in conjunction with an inflammatory insult, is the most common cause of death or disability in neonates. Therapeutic hypothermia (TH) is the standard of care for HI encephalopathy in term and near-term infants. However, TH may not always be available or efficacious, creating a need for novel or adjunctive neurotherapeutics. Using a near-term model of inflammation-sensitized HI brain injury in postnatal day (P) 17 ferrets, animals were randomized to either the control group ( = 43) or the HI-exposed groups: saline vehicle (Veh; = 42), Ur (uridine monophosphate, = 23), Epo (erythropoietin, = 26), or TH ( = 24) to test their respective therapeutic effects. Motor development was assessed from P21 to P42 followed by analysis of cortical anatomy, ex vivo MRI, and neuropathology. HI animals took longer to complete the motor assessments compared to controls, which was exacerbated in the Ur group. Injury resulted in thinned white matter tracts and narrowed cortical sulci and gyri, which was mitigated in Epo-treated animals in addition to normalization of cortical neuropathology scores to control levels. TH and Epo treatment also resulted in region-specific improvements in diffusion parameters on ex vivo MRI; however, TH was not robustly neuroprotective in any behavioral or neuropathological outcome measures. Overall, Ur and TH did not provide meaningful neuroprotection after inflammation-sensitized HI brain injury in the ferret, and Ur appeared to worsen outcomes. By comparison, Epo appears to provide significant, though not complete, neuroprotection in this model.
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http://dx.doi.org/10.3390/ijms22189841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469346PMC
September 2021

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.

J Pediatr 2021 Dec 26;239:117-125.e6. Epub 2021 Aug 26.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 24-27 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.
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http://dx.doi.org/10.1016/j.jpeds.2021.08.040DOI Listing
December 2021

Parental Enrollment Decision-Making for a Neonatal Clinical Trial.

J Pediatr 2021 Dec 14;239:143-149.e3. Epub 2021 Aug 14.

Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, WA; Department of Pediatrics, University of Washington School of Medicine, Seattle, WA.

Objective: 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.

Study Design: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jpeds.2021.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8610170PMC
December 2021

Enteral Iron Supplementation in Infants Born Extremely Preterm and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the Preterm Erythropoietin Neuroprotection Trial Randomized Controlled Trial.

J Pediatr 2021 11 27;238:102-109.e8. Epub 2021 Jul 27.

Department of Pediatrics, University of Washington, Seattle, WA.

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.
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http://dx.doi.org/10.1016/j.jpeds.2021.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629150PMC
November 2021

Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines.

JAMA Netw Open 2021 Jul 1;4(7):e2115998. Epub 2021 Jul 1.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle.

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.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.15998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264640PMC
July 2021

Intracranial Hemorrhage and 2-Year Neurodevelopmental Outcomes in Infants Born Extremely Preterm.

J Pediatr 2021 Nov 2;238:124-134.e10. Epub 2021 Jul 2.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA.

Objectives: To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 24 to 27 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.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551011PMC
November 2021

Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic-Ischemic Encephalopathy.

J Pediatr 2021 Oct 16;237:190-196. Epub 2021 Jun 16.

Department of Neurology, University of California San Francisco, San Francisco, CA.

Objective: 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.

Study Design: 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.

Results: 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.

Conclusions: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.

Trial Registration: ClinicalTrials.gov: NCT02811263.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.023DOI Listing
October 2021

Severe Acute Kidney Injury and Mortality in Extremely Low Gestational Age Neonates.

Clin J Am Soc Nephrol 2021 06 11;16(6):862-869. Epub 2021 Jun 11.

Division of Nephrology, University of Alabama at Birmingham, Children's of Alabama, Birmingham, Alabama.

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 <7 days before death. Landmark analyses examined the relationship of death with development of severe AKI.

Results: Severe AKI occurred in 168 of 900 (19%, 95% confidence interval, 17% to 20%) neonates, and stage 3 AKI occurred in 60 (7%, 95% confidence interval, 5% to 8%). Stage 3 AKI occurring 7 days before death (hazard ratio, 3.88; 95% confidence interval, 1.26 to 11.96), intraventricular hemorrhage (hazard ratio, 2.01; 95% confidence interval, 1.01 to 3.99) and sepsis (hazard ratio, 2.85; 95% confidence interval, 1.12 to 7.22) were all independently associated with death. Severe AKI occurring 7 days before death (hazard ratio, 2.21; 95% confidence interval, 0.92 to 5.26) was associated with death but not statistically significant. In a landmark analysis, after adjusting for potential confounders, late (after day 14 and before day 28) severe AKI was strongly associated with higher hazard of death (hazard ratio, 4.57; 95% confidence interval, 1.82 to 11.5).

Conclusions: Severe AKI occurs frequently in extremely low gestational age neonates. Stage 3 AKI is associated with mortality, and this association is present 7 days before death.
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http://dx.doi.org/10.2215/CJN.18841220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216626PMC
June 2021

Comparison of two markers of iron sufficiency and neurodevelopmental outcomes.

Early Hum Dev 2021 Jul 19;158:105395. Epub 2021 May 19.

Department of Pediatrics, University of Washington, Seattle, WA, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105395DOI Listing
July 2021

Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: rationale, protocol and harmonisation.

BMJ Open 2021 04 22;11(4):e043852. Epub 2021 Apr 22.

Department of Biostatistics, University of Washington, Seattle, Washington, USA.

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.
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http://dx.doi.org/10.1136/bmjopen-2020-043852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070884PMC
April 2021

Whole genome methylation and transcriptome analyses to identify risk for cerebral palsy (CP) in extremely low gestational age neonates (ELGAN).

Sci Rep 2021 03 5;11(1):5305. Epub 2021 Mar 5.

Pediatrics - Division of Neonatology, University of Washington, Seattle, WA, USA.

Preterm birth remains the leading identifiable risk factor for cerebral palsy (CP), a devastating form of motor impairment due to developmental brain injury occurring around the time of birth. We performed genome wide methylation and whole transcriptome analyses to elucidate the early pathogenesis of CP in extremely low gestational age neonates (ELGANs). We evaluated peripheral blood cell specimens collected during a randomized trial of erythropoietin for neuroprotection in the ELGAN (PENUT Trial, NCT# 01378273). DNA methylation data were generated from 94 PENUT subjects (n = 47 CP vs. n = 47 Control) on day 1 and 14 of life. Gene expression data were generated from a subset of 56 subjects. Only one differentially methylated region was identified for the day 1 to 14 change between CP versus no CP, without evidence for differential gene expression of the associated gene RNA Pseudouridine Synthase Domain Containing 2. iPathwayGuide meta-analyses identified a relevant upregulation of JAK1 expression in the setting of decreased methylation that was observed in control subjects but not CP subjects. Evaluation of whole transcriptome data identified several top pathways of potential clinical relevance including thermogenesis, ferroptossis, ribosomal activity and other neurodegenerative conditions that differentiated CP from controls.
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http://dx.doi.org/10.1038/s41598-021-84214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935929PMC
March 2021

Melatonin and/or erythropoietin combined with hypothermia in a piglet model of perinatal asphyxia.

Brain Commun 2021 1;3(1):fcaa211. Epub 2020 Dec 1.

Department of Neonatology, Institute for Women's Health, University College London, London, UK.

As therapeutic hypothermia is only partially protective for neonatal encephalopathy, safe and effective adjunct therapies are urgently needed. Melatonin and erythropoietin show promise as safe and effective neuroprotective therapies. We hypothesized that melatonin and erythropoietin individually augment 12-h hypothermia ( therapies) and hypothermia + melatonin + erythropoietin () leads to optimal brain protection. Following carotid artery occlusion and hypoxia, 49 male piglets (<48 h old) were randomized to: (i) hypothermia + vehicle ( = 12), (ii) hypothermia + melatonin (20 mg/kg over 2 h) ( = 12), (iii) hypothermia + erythropoietin (3000 U/kg bolus) ( = 13) or (iv) ( = 12). Melatonin, erythropoietin or vehicle were given at 1, 24 and 48 h after hypoxia-ischaemia. Hypoxia-ischaemia severity was similar across groups. Therapeutic levels were achieved 3 hours after hypoxia-ischaemia for melatonin (15-30 mg/l) and within 30 min of erythropoietin administration (maximum concentration 10 000 mU/ml). Compared to hypothermia + vehicle, we observed faster amplitude-integrated EEG recovery from 25 to 30 h with hypothermia + melatonin ( = 0.02) and hypothermia + erythropoietin ( = 0.033) and from 55 to 60 h with ( = 0.042). Magnetic resonance spectroscopy lactate/-acetyl aspartate peak ratio was lower at 66 h in hypothermia + melatonin ( = 0.012) and ( = 0.032). With hypothermia + melatonin, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells were reduced in sensorimotor cortex ( = 0.017) and oligodendrocyte transcription factor 2 labelled-positive counts increased in hippocampus ( = 0.014) and periventricular white matter ( = 0.039). There was no reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells with hypothermia + erythropoietin, but increased oligodendrocyte transcription factor 2 labelled-positive cells in 5 of 8 brain regions ( < 0.05). Overall, melatonin and erythropoietin were safe and effective adjunct therapies to hypothermia. Hypothermia + melatonin led to faster amplitude-integrated EEG recovery, amelioration of lactate/N-acetyl aspartate rise and reduction in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelled-positive cells in the sensorimotor cortex. Hypothermia + erythropoietin was in association with EEG recovery and was most effective in promoting oligodendrocyte survival. provided no added benefit over the therapies in this 72-h study. Melatonin and erythropoietin influenced cell death and oligodendrocyte survival differently, reflecting distinct neuroprotective mechanisms which may become more visible with longer-term studies. Staggering the administration of therapies with early melatonin and later erythropoietin (after hypothermia) may provide better protection; each therapy has complementary actions which may be time critical during the neurotoxic cascade after hypoxia-ischaemia.
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http://dx.doi.org/10.1093/braincomms/fcaa211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876304PMC
December 2020

Cytokine and chemokine responses to injury and treatment in a nonhuman primate model of hypoxic-ischemic encephalopathy treated with hypothermia and erythropoietin.

J Cereb Blood Flow Metab 2021 08 7;41(8):2054-2066. Epub 2021 Feb 7.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

Predicting long-term outcome in infants with hypoxic-ischemic encephalopathy (HIE) remains an ongoing clinical challenge. We investigated plasma biomarkers and their association with 6-month outcomes in a nonhuman primate model of HIE with or without therapeutic hypothermia (TH) and erythropoietin (Epo). Twenty-nine were randomized to control cesarean section (n = 7) or 20 min of umbilical cord occlusion (UCO, n = 22) with either no treatment (n = 11) or TH/Epo (n = 11). Initial injury severity was scored using 30-min arterial pH, base deficit, and 10-min Apgar score. Twenty-four plasma cytokines, chemokines, and growth factors were measured 3, 6, 24, 72, and 96 h after UCO. Interleukin 17 (IL-17) and macrophage-derived chemokine (MDC) differentiated the normal/mild from moderate/severe injury groups. Treatment with TH/Epo was associated with increased monocyte chemotactic protein-4 (MCP-4) at 3 h-6h, and significantly lower MCP-4 and MDC at 24 h-72h, respectively. IL-12p40 was lower at 24 h-72h in animals with death/cerebral palsy (CP) compared to survivors without CP. Baseline injury severity was the single best predictor of death/CP, and predictions did not improve with the addition of biomarker data. Circulating chemokines associated with the peripheral monocyte cell lineage are associated with severity of injury and response to therapy, but do not improve ability to predict outcomes.
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http://dx.doi.org/10.1177/0271678X21991439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327104PMC
August 2021

The Impact of Erythropoietin on Short- and Long-Term Kidney-Related Outcomes in Neonates of Extremely Low Gestational Age. Results of a Multicenter, Double-Blind, Placebo-Controlled Randomized Clinical Trial.

J Pediatr 2021 05 20;232:65-72.e7. Epub 2021 Jan 20.

Department of Pediatrics, University of Washington/Seattle Children's Hospital, Seattle, WA.

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 of 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/cystatin C values at days 0, 7, 9, and 14). At 22-26 months of cGA, 16% of the cohort had an estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m, 35.8% had urine albumin/creatinine ratio >30 mg/g, 23% had a systolic blood pressure (SBP) >95th percentile for age, and 40% had a diastolic blood pressure (DBP) >95th percentile for age. SBP >90th percentile occurred less often among recipients of erythropoietin (P < .04). This association remained even after controlling for gestational age, site, and sibship (aOR 0.6; 95% CI 0.39-0.92). We did not find statistically significant differences between treatment groups in eGFR, albumin/creatinine ratio, rates of SBP >95th percentile, or DBP >90th or >95th percentiles at the 2 year follow-up visit.

Conclusions: ELGANs have high rates of in-hospital AKI and kidney-related problems at 22-26 months of cGA. Recombinant erythropoietin 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 of cGA.
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http://dx.doi.org/10.1016/j.jpeds.2021.01.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093092PMC
May 2021

Parental Factors Associated With the Decision to Participate in a Neonatal Clinical Trial.

JAMA Netw Open 2021 01 4;4(1):e2032106. Epub 2021 Jan 4.

Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Importance: It remains poorly understood how parents decide whether to enroll a child in a neonatal clinical trial. This is particularly true for parents from racial or ethnic minority populations. Understanding factors associated with enrollment decisions may improve recruitment processes for families, increase enrollment rates, and decrease disparities in research participation.

Objective: To assess differences in parental factors between parents who enrolled their infant and those who declined enrollment for a neonatal randomized clinical trial.

Design, Setting, And Participants: This survey study conducted from July 2017 to October 2019 in 12 US level 3 and 4 neonatal intensive care units included parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial or who were eligible but declined enrollment. Data were analyzed October 2019 through July 2020.

Exposure: Parental choice of enrollment in neonatal clinical trial.

Main Outcomes And Measures: Percentages and odds ratios (ORs) of parent participation as categorized by demographic characteristics, self-assessment of child's medical condition, study comprehension, and trust in medical researchers. Survey questions were based on the hypothesis that parents who enrolled their infant in HEAL differ from those who declined enrollment across 4 categories: (1) infant characteristics and parental demographic characteristics, (2) perception of infant's illness, (3) study comprehension, and (4) trust in clinicians and researchers.

Results: Of a total 387 eligible parents, 269 (69.5%) completed the survey and were included in analysis. This included 183 of 242 (75.6%) of HEAL-enrolled and 86 of 145 (59.3%) of HEAL-declined parents. Parents who enrolled their infant had lower rates of Medicaid participation (74 [41.1%] vs 47 [55.3%]; P = .04) and higher rates of annual income greater than $55 000 (94 [52.8%] vs 30 [37.5%]; P = .03) compared with those who declined. Black parents had lower enrollment rates compared with White parents (OR, 0.35; 95% CI, 0.17-0.73). Parents who reported their infant's medical condition as more serious had higher enrollment rates (OR, 5.7; 95% CI, 2.0-16.3). Parents who enrolled their infant reported higher trust in medical researchers compared with parents who declined (mean [SD] difference, 5.3 [0.3-10.3]). There was no association between study comprehension and enrollment.

Conclusions And Relevance: In this study, the following factors were associated with neonatal clinical trial enrollment: demographic characteristics (ie, race/ethnicity, Medicaid status, and reported income), perception of illness, and trust in medical researchers. Future work to confirm these findings and explore the reasons behind them may lead to strategies for better engaging underrepresented groups in neonatal clinical research to reduce enrollment disparities.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.32106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804922PMC
January 2021

Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial.

Pediatr Res 2021 07 11;90(1):109-116. Epub 2021 Jan 11.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

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.
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http://dx.doi.org/10.1038/s41390-020-01273-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797706PMC
July 2021

High-Dose Erythropoietin in Extremely Low Gestational Age Neonates Does Not Alter Risk of Retinopathy of Prematurity.

Neonatology 2020 28;117(5):650-657. Epub 2020 Oct 28.

Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.

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.
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http://dx.doi.org/10.1159/000511262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855231PMC
August 2021

Effect of High-Dose Erythropoietin on Blood Transfusions in Extremely Low Gestational Age Neonates: Post Hoc Analysis of a Randomized Clinical Trial.

JAMA Pediatr 2020 10;174(10):933-943

Department of Biostatistics, University of Washington, Seattle.

Importance: 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.

Objectives: 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.

Design, Setting, And Participants: 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.

Interventions: 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.

Main Outcomes And Measures: Need for transfusion, transfusion numbers and volume, number of donor exposures, and lowest daily hematocrit level are presented herein.

Results: 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).

Conclusions And Relevance: 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.

Trial Registration: ClinicalTrials.gov Identifier: NCT01378273.
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http://dx.doi.org/10.1001/jamapediatrics.2020.2271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432302PMC
October 2020

The Resource Use Inflection Point for Safe NICU Discharge.

Pediatrics 2020 08;146(2)

Department of Pediatric Surgery, Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware.

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 <10% of the mean first-day NICU room cost and remained within this range through discharge (RU-IP). We compared days beyond an RU-IP, the total standardized cost of hospital days beyond the RU-IP, and the percentage of patients by hospital beyond the RU-IP.

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.
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http://dx.doi.org/10.1542/peds.2019-3708DOI Listing
August 2020

Prevalence of acute kidney injury (AKI) in extremely low gestational age neonates (ELGAN).

Pediatr Nephrol 2020 09 2;35(9):1737-1748. Epub 2020 Jun 2.

Department of Pediatrics, University of Washington/Seattle Children's Hospital, Seattle, WA, USA.

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: A total of 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.
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http://dx.doi.org/10.1007/s00467-020-04563-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093091PMC
September 2020

Erythropoietin in Preterm Infants. Reply.

N Engl J Med 2020 05;382(19):1862-1863

University of Washington, Seattle, WA

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http://dx.doi.org/10.1056/NEJMc2002493DOI Listing
May 2020

Consent Related Challenges for Neonatal Clinical Trials.

Am J Bioeth 2020 06;20(5):38-40

University of Washington School of Medicine.

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http://dx.doi.org/10.1080/15265161.2020.1745940DOI Listing
June 2020

A More Comprehensive Approach to the Neuroprotective Potential of Long-Chain Polyunsaturated Fatty Acids in Preterm Infants Is Needed-Should We Consider Maternal Diet and the n-6:n-3 Fatty Acid Ratio?

Front Pediatr 2019 10;7:533. Epub 2020 Jan 10.

Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA, United States.

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.
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http://dx.doi.org/10.3389/fped.2019.00533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965147PMC
January 2020

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

N Engl J Med 2020 01;382(3):233-243

From the University of Washington, Seattle (S.E.J., B.A.C., D.E.M., P.T.V., P.J.H.); Florida Hospital Orlando, Orlando (R.W.), the University of Florida, Gainesville (M.W.), South Miami Hospital, South Miami (J.E.P.), and Johns Hopkins All Children's Hospital, St. Petersburg (V.M.) - all in Florida; the University of Arkansas for Medical Sciences, Little Rock (S.E.C.); the University of Louisville, Louisville, KY (T.R.); Methodist Children's Hospital, San Antonio, TX (K.A.A.); Children's Hospital and Clinics of Minnesota (E.B.-S.) and University of Minnesota Masonic Children's Hospital (R.R., N.F.), Minneapolis, and Children's Minnesota, St. Paul (A.L.) - all in Minnesota; the University of Utah, Salt Lake City (M.B.); Maria Fareri Children's Hospital at Westchester Medical Center, Valhalla, NY (E.F.L.); Wake Forest School of Medicine, Winston-Salem (L.C.D.), and the University of North Carolina, Chapel Hill (T.M.O.) - both in North Carolina; Beth Israel Deaconess Medical Center (I.D.F.) and Boston University (K.K.) - both in Boston; Prentice Women's Hospital (J.Y.K.) and Children's Hospital of the University of Illinois (N.S.) - both in Chicago; Johns Hopkins University, Baltimore (M.M.G.), and the National Institute of Neurological Disorders and Stroke, Bethesda (A.L.H.) - both in Maryland; and the University of New Mexico, Albuquerque (R.K.O., J.L.).

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.).
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http://dx.doi.org/10.1056/NEJMoa1907423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060076PMC
January 2020
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