Neuroprotective Erythropoietin Research Articles

Longitudinal analysis of urinary I-FABP in extremely preterm infants that develop necrotizing enterocolitis.

Intestinal fatty acid binding protein (I-FABP) is an intestinal epithelial protein detectable in infants with necrotizing enterocolitis (NEC). The longitudinal behavior of I-FABP following NEC or its association with gastrointestinal or neurodevelopmental outcomes is unknown. In this secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, we compared infants with and without NEC. Urine I-FABP concentrations in matched infants (n = 70) were measured serially using ELISA and compared using paired analysis. In infants with NEC, the associations of I-FABP levels with short-term outcomes and neurodevelopmental outcomes at 22-26 months corrected age were determined using non-parametric analysis. Infants with NEC were more likely to have cholestasis, death or severe neurodevelopmental impairment, cerebral palsy, and lower Bayley-III motor scores. Baseline urinary I-FABP levels were similar between groups. When compared to controls, infants with NEC had urinary I-FABP concentrations that were higher at diagnosis (median 11 vs 2.6 ng/ml, p = 0.006) and lower post-NEC (median 1 vs 5 ng/ml, p = 0.002). Diagnosis I-FABP levels were not associated with gastrointestinal or neurodevelopmental outcomes at 22-26 months corrected age. In extremely preterm infants, urinary I-FABP was elevated at NEC diagnosis and lower post-NEC compared to matched controls. I-FABP levels were not associated with adverse gastrointestinal or neurodevelopmental outcomes. Urinary intestinal fatty acid binding protein (I-FABP) levels are increased at diagnosis of NEC and fall to below baseline after NEC in extremely preterm infants. Urine I-FABP levels at NEC diagnosis are not associated with cholestasis, intestinal stricture or obstruction, need for additional intestinal surgery after NEC, or neurodevelopmental outcomes at 22-26 months corrected age. Urine I-FABP levels may be useful in the diagnosis of NEC. Diagnostic I-FABP levels do not predict short-term gastrointestinal or neurodevelopmental outcomes after NEC.

Association of delayed cord clamping with acute kidney injury and two-year kidney outcomes in extremely premature neonates: a secondary analysis of the preterm erythropoietin neuroprotection trial (PENUT).

Delayed cord clamping (DCC) occurs in most preterm births. Evaluate the association of DCC with acute kidney injury (AKI) and two-year kidney outcomes. Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates born 240/7 to 276/7 weeks gestation. AKI and two year kidney outcomes were compared in neonates with DCC ( ≥ 30 s after delivery) to those with early cord clamping (ECC) (<30 s after delivery). The incidence and severity of AKI did not differ between the DCC and ECC groups (aOR 1.17 [95%CI 0.76-1.80]). At two years corrected age, DCC was associated with a 4.5-fold increased adjusted odds of estimated glomerular filtration rate (eGFR) <90 mL/min/1.73m2. No significant associations were noted between DCC and albuminuria or elevatedblood pressure. DCC was not associated with decreased neonatal AKI, but was associated with higher adjusted odds of eGFR <90 mL/min/1.73m2 at two years.

Association of delayed cord clamping with acute kidney injury and two-year kidney outcomes in extremely premature neonates: a secondary analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT).

Delayed cord clamping (DCC) occurs in most preterm births. Evaluate the association of DCC with acute kidney injury (AKI) and two-year kidney outcomes. Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates born 240/7 to 276/7 weeks' gestation. AKI and two year kidney outcomes were compared in neonates with DCC (≥30 seconds after delivery) to those with early cord clamping (ECC) (<30 seconds after delivery). The incidence and severity of AKI did not differ between the DCC and ECC groups (aOR 1.17 [95%CI 0.76-1.80]). At two years corrected age, DCC was associated with a 4.5-fold times increased adjusted odds of eGFR <90 mL/min/1.73m2. No significant associations were noted between DCC and albuminuria or elevated BP. DCC was not associated with decreased neonatal AKI, but was associated with higher adjusted odds of eGFR <90 mL/min/1.73m2 at two years.

Perinatal risk factors associated with acute kidney injury severity and duration among infants born extremely preterm.

We evaluated time-varying perinatal risk factors associated with early (≤7 post-natal days) and late (>7 post-natal days) severe acute kidney injury (AKI) occurrence and duration. A secondary analysis of Preterm Erythropoietin Neuroprotection Trial data. We defined severe AKI (stage 2 or 3) per neonatal modified Kidney Disease: Improving Global Outcomes criteria. Adjusted Cox proportional hazards models were conducted with exposures occurring at least 72 h before severe AKI. Adjusted negative binomial regression models were completed to evaluate risk factors for severe AKI duration. Of 923 participants, 2% had early severe AKI. In the adjusted model, gestational diabetes (adjusted HR (aHR) 5.4, 95% CI 1.1-25.8), non-steroidal anti-inflammatory drugs (NSAIDs) (aHR 3.2, 95% CI 1.0-9.8), and vancomycin (aHR 13.9, 95% CI 2.3-45.1) were associated with early severe AKI. Late severe AKI occurred in 22% of participants. Early severe AKI (aHR 2.5, 95% CI 1.1-5.4), sepsis (aHR 2.5, 95% CI 1.4-4.4), vasopressors (aHR 2.9, 95% CI 1.8-4.6), and diuretics (aHR 2.6, 95% CI 1.9-3.6) were associated with late severe AKI. Participants who had necrotizing enterocolitis or received NSAIDs had longer severe AKI duration. We identified major risk factors for severe AKI that can be the focus of future research. Time-dependent risk factors for severe acute kidney injury (AKI) and its duration are not well defined among infants born <28 weeks' gestation. Over 1 in 5 infants born <28 weeks' gestation experienced severe AKI, and this study identified several major time-dependent perinatal risk factors occurring within 72 h prior to severe AKI. This study can support efforts to develop risk stratification and clinical decision support to help mitigate modifiable risk factors to reduce severe AKI occurrence and duration.

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm

Infants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes. To evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years' corrected age in a cohort of infants born extremely preterm. An observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023. Any platelet transfusion during neonatal intensive care unit hospitalization. The primary composite outcome was death or severe NDI evaluated at 2 years' corrected age using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods. Of the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome. The findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years' corrected age, although the possibility of residual confounding by indication cannot be excluded.

Caffeine and kidney function at two years in former extremely low gestational age neonates.

Extremely low gestational age neonates (ELGANs) are at risk for chronic kidney disease. The long-term kidney effects of neonatal caffeine are unknown. We hypothesize that prolonged caffeine exposure will improve kidney function at 22-26 months. Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates <28 weeks' gestation. Participants included if any kidney outcomes were collected at 22-26 months corrected age. Exposure was post-menstrual age of caffeine discontinuation. 'reduced eGFR' <90 ml/min/1.73 m2, 'albuminuria' (>30 mg albumin/g creatinine), or 'elevated blood pressure' (BP) >95th %tile. A general estimating equation logistic regression model stratified by bronchopulmonary dysplasia (BPD) status was used. 598 participants had at least one kidney metricat follow up. Within the whole cohort, postmenstrual age of caffeine discontinuation was not associated with any abnormal measures of kidney function at 2 years. In the stratified analysis, for each additional week of caffeine, the no BPD group had a 21% decreased adjusted odds of eGFR <90ml/min/1.73m2 (aOR 0.78; CI 0.62-0.99) and the BPD group had a 15% increased adjusted odds of elevated BP (aOR 1.15; CI: 1.05-1.25). Longer caffeine exposure during the neonatal period is associated with differential kidney outcomes at 22-26 months dependent on BPD status. In participants born <28 weeks' gestation, discontinuation of caffeine at a later post menstrual age was not associated with abnormal kidney outcomes at 22-26 months corrected age. When assessed at 2 years of age, later discontinuation of caffeine in children born <28 weeks' gestation was associated with a greater risk of reduced eGFR in those without a history of BPD and an increased odds of hypertension in those with a history of BPD. More work is necessary to understand the long-term impact of caffeine on the developing kidney.

Acute Kidney Injury Defined by Fluid-Corrected Creatinine in Premature Neonates

Acute kidney injury (AKI) and disordered fluid balance are common in premature neonates; a positive fluid balance dilutes serum creatinine, and a negative fluid balance concentrates serum creatinine, both of which complicate AKI diagnosis. Correcting serum creatinine for fluid balance may improve diagnosis and increase diagnostic accuracy for AKI. To determine whether correcting serum creatinine for fluid balance would identify additional neonates with AKI and alter the association of AKI with short-term and long-term outcomes. This study was a post hoc cohort analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3, randomized clinical trial of erythropoietin, conducted at 19 academic centers and 30 neonatal intensive care units in the US from December 2013 to September 2016. Participants included extremely premature neonates born at less than 28 weeks of gestation. Data analysis was conducted in December 2022. Diagnosis of fluid-corrected AKI during the first 14 postnatal days, calculated using fluid-corrected serum creatinine (defined as serum creatinine multiplied by fluid balance [calculated as percentage change from birth weight] divided by total body water [estimated 80% of birth weight]). The primary outcome was invasive mechanical ventilation on postnatal day 14. Secondary outcomes included death, hospital length of stay, and severe bronchopulmonary dysplasia (BPD). Categorical variables were analyzed by proportional differences with the χ2 test or Fisher exact test. The t test and Wilcoxon rank sums test were used to compare continuous and ordinal variables, respectively. Odds ratios (ORs) and 95% CIs for the association of exposure with outcomes of interest were estimated using unconditional logistic regression models. A total of 923 premature neonates (479 boys [51.9%]; median [IQR] birth weight, 801 [668-940] g) were included, of whom 215 (23.3%) received a diagnosis of AKI using uncorrected serum creatinine. After fluid balance correction, 13 neonates with AKI were reclassified as not having fluid-corrected AKI, and 111 neonates previously without AKI were reclassified as having fluid-corrected AKI (ie, unveiled AKI). Therefore, fluid-corrected AKI was diagnosed in 313 neonates (33.9%). Neonates with unveiled AKI were similar in clinical characteristics to those with AKI whose diagnoses were made with uncorrected serum creatinine. Compared with those without AKI, neonates with unveiled AKI were more likely to require ventilation (81 neonates [75.0%] vs 254 neonates [44.3%] and have longer hospital stays (median [IQR], 102 [84-124] days vs 90 [71-110] days). In multivariable analysis, a diagnosis of fluid-corrected AKI was associated with increased odds of adverse clinical outcomes, including ventilation (adjusted OR, 2.23; 95% CI, 1.56-3.18) and severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64). In this post hoc cohort study of premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI and was associated with increased odds of adverse clinical outcomes, including ventilation and BPD. Failing to correct serum creatinine for fluid balance underestimates the prevalence and impact of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance. ClinicalTrials.gov Identifier: NCT01378273.

Association of Fluid Balance With Short- and Long-term Respiratory Outcomes in Extremely Premature Neonates

Extremely low gestational age neonates are at risk of disorders of fluid balance (FB), defined as change in fluid weight over a specific period. Few data exist on the association between FB and respiratory outcomes in this population. To describe FB patterns and evaluate the association of FB with respiratory outcomes in a cohort of extremely low gestational age neonates. This study is a secondary analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3 placebo-controlled randomized clinical trial of erythropoietin in extremely premature neonates conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 874 extremely premature neonates born at 24 to 27 weeks' gestation who were enrolled in the PENUT study. Secondary analysis was performed in November 2021. Primary exposure was peak FB during the first 14 postnatal days. The FB was calculated as percent change in weight from birth weight (BW) as a surrogate for FB. The primary outcome was mechanical ventilation on postnatal day 14. The secondary outcome was a composite of severe bronchopulmonary dysplasia (BPD) or death. A total of 874 neonates (449 [51.4%] male; mean [SD] BW, 801 [188] g; 187 [21.4%] Hispanic, 676 [77.3%] non-Hispanic, and 11 [1.3%] of unknown ethnicity; 226 [25.9%] Black, 569 [65.1%] White, 51 [5.8%] of other race, and 28 [3.2%] of unknown race) were included in this analysis. Of these 874 neonates, 458 (52.4%) received mechanical ventilation on postnatal day 14, and 291 (33.3%) had severe BPD or had died. Median peak positive FB was 11% (IQR, 4%-20%), occurring on postnatal day 13 (IQR, 9-14). A total of 93 (10.6%) never decreased below their BW. Neonates requiring mechanical ventilation at postnatal day 14 had a higher peak FB compared with those who did not require mechanical ventilation (15% above BW vs 8% above BW, P < .001). On postnatal day 3, neonates requiring mechanical ventilation were more likely to have a higher FB (5% below BW vs 8% below BW, P < .001). The median time to return to BW was shorter in neonates who received mechanical ventilation (7 vs 8 days, P < .001) and those with severe BPD (7 vs 8 days, P < .001). After adjusting for confounding variables, for every 10% increase in peak FB during the first 14 postnatal days, there was 103% increased odds of receiving mechanical ventilation at postnatal day 14 (adjusted odds ratio, 2.03; 95% CI, 1.64-2.51). In this secondary analysis of a randomized clinical trial, peak FB was associated with mechanical ventilation on postnatal day 14 and severe BPD or death. Fluid balance in the first 3 postnatal days and time to return to BW may be potential targets to help guide management and improve respiratory outcomes. ClinicalTrials.gov Identifier: NCT01378273.

Cytokine Receptor-Like Factor 3 Negatively Regulates Antiviral Immunity by Promoting the Degradation of TBK1 in Teleost Fish.

The cytokine receptor-like factor 3 (Crlf3) belongs to the orphan class I cytokine receptors and is identified as a neuroprotective erythropoietin receptor. In previous studies of Crlf3, few focused on its role in innate immunity. Therefore, this study explored the regulatory role of Crlf3 in innate immunity. TANK-binding kinase 1 (TBK1) is a vital adaptor protein for the activation of the RLRs-MVAS-IRF3 antiviral signaling axis; thus, its expression and activity must be tightly regulated to maintain immune homeostasis and avoid undesirable effects. Here, we report that Crlf3 is a negative regulator of type I interferon production. The expression of Crlf3 is induced by poly(I·C) or Siniperca chuatsi rhabdovirus (SCRV) treatment. Silencing of Crlf3 enhanced poly(I·C)- and SCRV-induced type I interferon production, whereas overexpression of Crlf3 suppressed type I interferon production. Mechanistically, Crlf3 interacted with TBK1 via its N domain and then inhibited type I interferon production by promoting TBK1 proteasomal degradation through K48-linked polyubiquitination. Our study shows that Crlf3 is a key factor for viral escape from innate antiviral immunity in fish and provides a new perspective on mammalian resistance to viral invasion. IMPORTANCE The expression of Crlf3 was upregulated with SCRV invasion, which proved that Crlf3 was involved in the regulation of the antiviral immune response. In this study, we found that the existence of Crlf3 promoted the replication of SCRV. Therefore, it is reasonable to believe that SCRV evades innate immune attack with the assistance of Crlf3. In addition, we report that Crlf3 negatively regulates interferon (IFN) induction by promoting the degradation of TBK1 in fish. We showed that Crlf3 is evenly distributed in the cytoplasm and interacts with TBK1. Further studies showed that Crlf3 specifically mediates K48-linked ubiquitination of TBK1 and promotes TBK1 degradation, resulting in a marked inhibition of retinoic acid-inducible gene I (RIG-I) downstream signaling.

Taking Stock After Another Negative Erythropoietin Neuroprotection Trial

Sven Wellmann, MD; Cornelia F. Hagmann, MD, PhD; Stefanie von Felten, PhD; Leonard Held, PhD; Katrin Klebermass-Schrehof, MD; Anita C. Truttmann, MD, PhD; Claudia Knöpfli, MSc; Jean-Claude Fauchère, MD, PhD; Christoph Bührer, MD; Hans Ulrich Bucher, MD, PhD; Christoph M. Rüegger, MD; Erythropoietin for the Repair of Cerebral Injury in Very Preterm Infants (EpoRepair) Investigators; Philipp Meyer; Gabriel Konetzny; Corinne Däster; Sven M Schulzke; Severin Kasser; Roland Gerull; Mathias Nelle; Benedikt Bubl; Walter Bär; Brigitte Scharrer; Thomas Riedel; Jean-François Tolsa; Bjarte Rogdo; Irene Hoigne; André Birkenmaier; Giancarlo Natalucci; Angelika Berger; Alexandra Thajer

Blood pressure values and hypotension management in extremely preterm infants: a multi-center study.

To describe high/low daily blood pressures (BP) and variability in BP management with vasoactive infusions (VI) and/or hydrocortisone (HC) in extremely preterm infants. Analysis of data from 24-27 weeks' gestation infants in the Preterm Erythropoietin Neuroprotection (PENUT) Trial. Daily high/low BPs, the use of VI and/or HC, and adverse outcomes were compared descriptively and using regression models. 936 infants were included; 64% untreated, 20% VI, 3% HC, and 13% VI + HC. BP ranges are described for the 602 untreated infants. Considerable inter- and intra-center variability was demonstrated in the rate of VI and/or HC use and the lowest BP on the day of VI or HC initiation. Despite published expert opinion guidance regarding BP management in extremely preterm infants, our results suggest a continued lack of consensus result in both inter- and intra-center variability in practice. Well-designed studies in the field are urgently needed.

Dexamethasone, Prednisolone, and Methylprednisolone Use and 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants

Practice variability exists in the use of corticosteroids to treat or prevent bronchopulmonary dysplasia in extremely preterm infants, but there is limited information on longer-term impacts. To describe the use of corticosteroids in extremely preterm infants and evaluate the association with neurodevelopmental outcomes. This cohort study was a secondary analysis of data from the Preterm Erythropoietin Neuroprotection (PENUT) randomized clinical trial, conducted at 19 participating sites and 30 neonatal intensive care units (NICUs) in the US. Inborn infants born between 24 0/7 and 27 6/7 weeks gestational age between December 2013 and September 2016 were included in analysis. Data analysis was conducted between February 2021 and January 2022. Cumulative dose of dexamethasone and duration of therapy for dexamethasone and prednisolone or methyl prednisolone were evaluated. Demographic and clinical characteristics were described in infants who did or did not receive corticosteroids of interest and survived to discharge. Neurodevelopmental outcomes at 2 years of age were evaluated using the Bayley Scales of Infant Development-Third Edition (BSID-III) at corrected age 2 years. A total of 828 extremely preterm infants (403 [49%] girls; median [IQR] gestational age, 26 [25-27] weeks) born at 19 sites who survived to discharge were included in this analysis, and 312 infants (38%) were exposed to at least 1 corticosteroid of interest during their NICU stay, including 279 exposed to dexamethasone, 137 exposed to prednisolone or methylprednisolone, and 79 exposed to both. Exposed infants, compared with nonexposed infants, had a lower birth weight (mean [SD], 718 [168] g vs 868 [180] g) and were born earlier (mean [SD] gestational age, 25 [1] weeks vs 26 [1] weeks). The median (IQR) start day was 29 (20-44) days for dexamethasone and 53 (30-90) days for prednisolone or methylprednisolone. The median (IQR) total days of exposure was 10 (5-15) days for dexamethasone and 13 (6-25) days for prednisolone or methylprednisolone. The median (IQR) cumulative dose of dexamethasone was 1.3 (0.9-2.8) mg/kg. After adjusting for potential confounders, treatment with dexamethasone for longer than 14 days was associated with worse neurodevelopmental outcomes, with mean scores in BSID-III 7.4 (95% CI, -12.3 to -2.5) points lower in the motor domain (P = .003) and 5.8 (95% CI, -10.9 to -0.6) points lower in the language domain (P = .03), compared with unexposed infants. These findings suggest that long duration and higher cumulative dose of dexamethasone were associated with worse neurodevelopmental scores at corrected age 2 years. Potential unmeasured differences in the clinical conditions of exposed vs unexposed infants may contribute to these findings. Improved standardization of treatment and documentation of indications would facilitate replication studies.

Deaths in a Modern Cohort of Extremely Preterm Infants From the Preterm Erythropoietin Neuroprotection Trial

Understanding why and how extremely preterm infants die is important for practitioners caring for these infants. To examine risk factors, causes, timing, and circumstances of death in a modern cohort of extremely preterm infants. A retrospective cohort review of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial between December 13, 2013, and September 26, 2016, was conducted. A total of 941 infants born between 24 0/7 and 27 6/7 weeks of gestation enrolled at 19 US sites comprising 30 neonatal intensive care units were included. Data analysis was performed from October 16, 2020, to December 1, 2021. Risk factors, proximal causes, timing, and circumstances of in-hospital death. Of the 941 enrolled infants, 108 died (11%) before hospital discharge: 38% (n = 41) at 24 weeks' gestation, 30% (n = 32) at 25 weeks' gestation, 19% (n = 20) at 26 weeks' gestation, and 14% (n = 15) at 27 weeks' gestation. An additional 9 infants (1%) died following hospital discharge. In descending order, the primary causes of death included respiratory distress or failure, pulmonary hemorrhage, necrotizing enterocolitis, catastrophic intracranial hemorrhage, sepsis, and sudden unexplained death. Fifty percent of deaths occurred within the first 10 days after birth. The risk of death decreased with day of life and postmenstrual age such that an infant born at 24 weeks' gestation who survived 14 days had the same risk of death as an infant born at 27 weeks' gestation: conditional proportional risk of death, 0.08 (95% CI, 0.03-0.13) vs 0.06 (95% CI, 0.01-0.11). Preterm labor was associated with a decreased hazard of death (hazard ratio [HR], 0.45; 95% CI, 0.31-0.66). Infant clinical factors associated with death included birth weight below the tenth percentile for gestational age (HR, 2.11; 95% CI, 1.38-3.22), Apgar score less than 5 at 5 minutes (HR, 2.19; 95% CI, 1.48-3.24), sick appearance at birth (HR, 2.49; 95% CI, 1.69-3.67), grade 2b-3 necrotizing enterocolitis (HR, 7.41; 95% CI, 5.14-10.7), pulmonary hemorrhage (HR, 10.0; 95% CI, 6.76-18.8), severe intracranial hemorrhage (HR, 4.60; 95% CI, 3.24-5.63), and severe sepsis (HR, 4.93; 95% CI, 3.67-7.21). Fifty-one percent of the infants received comfort care before death. In this cohort study, an association between mortality and gestational age at birth was noted; however, for each week that an infant survived, their risk of subsequent death approximated the risk observed in infants born 1 to 2 weeks later, suggesting the importance of an infant's postmenstrual age. This information may be useful to include in counseling of families regarding prognosis of survival.

Age and genotype dependent erythropoietin protection in COVID-19.

Erythropoietin (EPO) is the main mediator of erythropoiesis and an important tissue protective hormone that appears to mediate an ancestral neuroprotective innate immune response mechanism at an early age. When the young brain is threatened-prematurity, neonatal hyperbilirubinemia, malaria- EPO is hyper-secreted disproportionately to any concurrent anemic stimuli. Under eons of severe malarial selection pressure, neuroprotective EPO augmenting genetic determinants such as the various hemoglobinopathies, and the angiotensin converting enzyme (ACE) I/D polymorphism, have been positively selected. When malarial and other cerebral threats abate and the young child survives to adulthood, EPO subsides. Sustained high ACE and angiotensin II (Ang II) levels through the ACE D allele in adulthood may then become detrimental as witnessed by epidemiological studies. The ubiquitous renin angiotensin system (RAS) influences the α-klotho/fibroblast growth factor 23 (FGF23) circuitry, and both are interconnected with EPO. Here we propose that at a young age, EPO augmenting genetic determinants through ACE D allele elevated Ang II levels in some or HbE/beta thalassemia in others would increase EPO levels and shield against coronavirus disease 2019, akin to protection from malaria and dengue fever. Human evolution may use ACE2 as a “bait” for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to gain cellular entry in order to trigger an ACE/ACE2 imbalance and stimulate EPO hypersecretion using tissue RAS, uncoupled from hemoglobin levels. In subjects without EPO augmenting genetic determinants at any age, ACE2 binding and internalization upon SARS-CoV-2 entry would trigger an ACE/ACE2 imbalance, and Ang II oversecretion leading to protective EPO stimulation. In children, low nasal ACE2 Levels would beneficially augment this imbalance, especially for those without protective genetic determinants. On the other hand, in predisposed adults with the ACE D allele, ACE/ACE2 imbalance, may lead to uncontrolled RAS overactivity and an Ang II induced proinflammatory state and immune dysregulation, with interleukin 6 (IL-6), plasminogen activator inhibitor, and FGF23 elevations. IL-6 induced EPO suppression, aggravated through co-morbidities such as hypertension, diabetes, obesity, and RAS pharmacological interventions may potentially lead to acute respiratory distress syndrome, cytokine storm and/or autoimmunity. HbE/beta thalassemia carriers would enjoy protection at any age as their EPO stimulation is uncoupled from the RAS system. The timely use of rhEPO, EPO analogs, acetylsalicylic acid, bioactive lipids, or FGF23 antagonists in genetically predisposed individuals may counteract those detrimental effects.

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

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.

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

BackgroundIn 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.MethodsPlasma 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).FindingsElevated 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.InterpretationElevated 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.FundingPENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).

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

To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2years corrected age. The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2years 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. 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 >7days; 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 2years of corrected age. 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 2years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

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

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). 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 2years were included in this study. The associations between enteral iron dose at 60 and 90days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. In total, 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged from 0 to 14.7mg/kg/d (IQR 2.1-5.8mg/kg/d) at day 60, with a mean of 3.6mg/kg/d in infants treated with placebo and 4.8mg/kg/d in infants treated with Epo. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60days, with an effect size of 0.77 BSID points per 50mg/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 90days were not significant. The effect size in the infants treated with Epo compared with placebo was consistently greater. A positive association was seen between iron dose at 60days 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. Clinicaltrials.gov: NCT01378273.

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

Extremely preterm (EP) infants frequently receive opioids and/or benzodiazepines, but these drugs' association with neurodevelopmental outcomes is poorly understood. 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. 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. Short (ie, ≤7 days) and prolonged (ie, >7 days) exposure to opioids and/or benzodiazepines during NICU stay. Cognitive, language, and motor development scores were assessed using the Bayley Scales of Infant Development-Third Edition (BSID-III). 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. 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.

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

To determine the incidence, timing, progression, and risk factors for intracranial hemorrhage (ICH) in infants 240/7 to 276/7weeks of gestational age and to characterize the association between ICH and death or neurodevelopmental impairment (NDI) at 2years of corrected age. Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial had serial cranial ultrasound scans performed on day 1, day 7-9, and 36weeks 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 2years of corrected age. 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 36weeks were associated with previous ICH at day 7-9. Bilateral Grade 2, any Grade 3, and any Grade 4 ICH at 7-9days or 36weeks 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. 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.