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.
We aimed to evaluate two markers of iron sufficiency, ferritin and zinc protoporphyrin-to-heme ratios (ZnPP/H), with neurodevelopmental outcomes.
This is a retrospective cohort study.
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.
Associations between iron markers (minimum, maximum and median ferritin and ZnPP/H) and BSID-III score at 24 months were assessed.
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.
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.
•Iron deficiency during the neonatal period is associated with worse neurodevelopmental outcomes.•This study suggests that ZnPP/H is more consistently correlated with neurodevelopmental outcome than ferritin.•Of the two methods evaluated, ZnPP/H may be preferred to adjust neonatal iron supplementation.
To evaluate whether extremely preterm infants regulate iron status via hepcidin.
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.
The correlation (r) between Uhep/UCr and serum markers of iron status (ferritin and zinc protoporphyrin-to-heme ratio ZnPP/H) and iron dose was assessed. A total of 243 urine samples from 76 infants born at 24-276/7 weeks gestation were analyzed. The median Uhep/UCr concentration was 0.3, 1.3, 0.4, and 0.1 ng/mg at baseline, 2 weeks, 4 weeks, and 12 weeks, respectively, in placebo-treated infants. The median Uhep/UCr value in Epo-treated infants were not significantly different, with the exception of the value at the 2-week time point (median Uhep/UCr, 0.1 ng/mg; P < .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).
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.
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.
Complications of prematurity often disrupt normal brain development and/or cause direct damage to the developing brain, resulting in poor neurodevelopmental outcomes. Physiologically relevant animal ...models of perinatal brain injury can advance our understanding of these influences and thereby provide opportunities to develop therapies and improve long-term outcomes. While there are advantages to currently available small animal models, there are also significant drawbacks that have limited translation of research findings to humans. Large animal models such as newborn pig, sheep and nonhuman primates have complex brain development more similar to humans, but these animals are expensive, and developmental testing of sheep and piglets is limited. Ferrets (Mustela putorius furo) are born lissencephalic and undergo postnatal cortical folding to form complex gyrencephalic brains. This review examines whether ferrets might provide a novel intermediate animal model of neonatal brain disease that has the benefit of a gyrified, altricial brain in a small animal. It summarizes attributes of ferret brain growth and development that make it an appealing animal in which to model perinatal brain injury. We postulate that because of their innate characteristics, ferrets have great potential in neonatal neurodevelopmental studies.
High-dose recombinant erythropoietin is neuroprotective in animal models of neonatal brain injury. Extremely low birth weight infants are at high risk for brain injury and neurodevelopmental problems ...and might benefit from recombinant erythropoietin. We designed a phase I/II trial to test the safety and determine the pharmacokinetics of high-dose recombinant erythropoietin in extremely low birth weight infants.
In a prospective, dose-escalation, open-label trial, we compared 30 infants who were treated with high-dose recombinant erythropoietin with 30 concurrent control subjects. Eligible infants were <24 hours old, <or=1000 g birth weight, and <or=28 weeks of gestation and had an umbilical artery catheter in place. Each infant received 3 intravenous doses of 500, 1000, or 2500 U/kg at 24-hour intervals beginning on day 1 of age. Blood samples were collected at scheduled intervals to determine recombinant erythropoietin pharmacokinetics. Safety parameters were also evaluated. In the concurrent control group, only clinical data were collected.
Mean erythropoietin concentrations 30 minutes after recombinant erythropoietin infusion were 5973 +/- 266, 12291 +/- 403, and 34197 +/- 1641 mU/mL after 500, 1000, or 2500 U/kg, respectively. High-dose recombinant erythropoietin followed nonlinear pharmacokinetics as a result of decreasing clearance from the lowest dosage (17.3 mL/hour per kg for 500 U/kg) to the highest dosage (8.2 mL/hour per kg for 2500 U/kg). Steady state was achieved within 24 to 48 hours. Both 1000 and 2500 U/kg recombinant erythropoietin produced peak serum erythropoietin concentrations that were comparable to neuroprotective concentrations that previously were seen in experimental animals. No excess adverse events occurred in the recombinant erythropoietin-treated infants compared with control infants.
Early high-dose recombinant erythropoietin is well tolerated by extremely low birth weight infants, causing no excess morbidity or mortality. Recombinant erythropoietin dosages of 1000 and 2500 U/kg achieved neuroprotective serum levels.
There is a critical need for development of physiological biomarkers in infants with birth asphyxia to identify the physiologic response to therapies in real time. This is an ancillary single site ...study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (Wu et al., 2022 1) to measure neurovascular coupling (NVC) non-invasively during an ongoing blinded randomized trial.
Neonates who randomized in the HEAL enrolled at a single-center Level III Neonatal Intensive Care Unit were recruited between 2017 and 2019. Neurodevelopmental impairment was blinded and defined as any of the following: cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition (BSID-III), Gross Motor Function Classification Score (GMFCS) ≥1.
All twenty-seven neonates enrolled in HEAL were recruited and 3 died before complete recording. The rank-based analysis of covariance models demonstrated lack of difference in NVC between the two groups (Epo versus Placebo) that was consistent with the observed lack of effect on neurodevelopmental outcomes.
We demonstrate no difference in neurovascular coupling after Epo administration. These findings are consistent with overall negative trial results. Physiological biomarkers can help elucidate mechanisms of neuroprotective therapies in real time in future trials.
•Non-invasive neurovascular coupling is feasible during a new trial of neuroprotection.•Neurovascular coupling is unchanged before/after Epo administration.•This approach, if replicated, can elucidate mechanisms of neuroprotective therapies.
Erythropoietin in Preterm Infants. Reply Juul, Sandra E; Comstock, Bryan A; Heagerty, Patrick J
The New England journal of medicine,
05/2020, Letnik:
382, Številka:
19
Journal Article
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.
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.
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).
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.
To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs).
Five ...hundred infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypothermia were randomized to Epo or placebo on days 1, 2, 3, 4, and 7. Pretreatment and posttreatment SAEs were compared with adjusted generalized linear models, with posttreatment models adjusted for the presence of a pretreatment SAE. Clinical risk factors and potential mechanisms for SAEs were also examined.
The rate of experiencing at least one posttreatment SAE did not significantly differ between groups (adjusted relative risk aRR, 95% CI: 1.17, 0.92-1.49); however, posttreatment thrombosis was identified more often in the Epo group (n = 6, 2.3%) than the placebo group (n = 1, 0.4%; aRR, 95% CI: 5.09, 1.32-19.64). The rate of posttreatment intracranial hemorrhage identified at the treatment sites by either ultrasound or magnetic resonance imaging was slightly elevated in the Epo group (n = 61, 24%) but not significantly different from the placebo group (n = 46, 19%; aRR, 95% CI: 1.21, 0.85, 1.72).
A small increased risk of major thrombotic events was identified in the Epo treatment group.
NCT02811263.
Background
Acute kidney injury (AKI) is common and is associated with poor clinical outcomes in premature neonates. Urine biomarkers hold the promise to improve our understanding and care of patients ...with kidney disease. Because kidney maturation and gender can impact urine biomarker values in extremely low gestational age neonates (ELGANs), careful control of gestational age (GA) and time is critical to any urine biomarker studies in neonates.
Methods
To improve our understanding of the potential use of urine biomarkers to detect AKI during the first postnatal weeks, we performed a nested case–control study to evaluate 21 candidate urine AKI biomarkers. Cases include 20 ELGANs with severe AKI. Each case was matched with 2 controls for the same GA week (rounded down to the nearest week), gender, and birth weight (BW) (± 50 g).
Results
Urine cystatin C, creatinine, ghrelin, fibroblast growth factor-23 (FGF23), tissue metalloproteinase 2 (TIMP2) and vascular endothelial growth factor A (VEGFa) concentrations were higher in ELGANs with early severe AKI compared to matched control subjects without AKI. Urine epidermal growth factor (EGF) and uromodulin (UMOD) concentrations are lower in cases than controls. Interleukin (IL)-15 was lower on day 1, but higher on day 8 in cases than controls; while VEGFa was lower on day 1, but higher on day 5 in cases than controls.
Conclusion
Urine biomarkers hold the promise to improve our ability to reliably detect kidney injury. Interventional studies are needed to determine the biomarkers’ ability to predict outcomes, enhance AKI phenotypes, and improve timely interventions which can prevent the sequalae of AKI in ELGANs.
Graphical abstract
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Supplementary information
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