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Background: Phlebotomy-induced anemia (PIA) is universal and variable in degree among preterm infants and may contribute to neurodevelopmental risk. In mice, PIA causes brain tissue hypoxia, iron deficiency, and long-term sex-dependent neurobehavioral abnormalities. The neuroregulatory molecular pathways disrupted by PIA underlying these effects are unknown., Methods: Male and female pups were phlebotomized daily from postnatal day (P)3-P14 via facial venipuncture to target hematocrits of 25% (moderate, mPIA) and 18% (severe, sPIA). P14 hippocampal RNA from non-bled control and PIA mice was sequenced by next-generation sequencing to identify differentially expressed genes (DEGs) that were analyzed using Ingenuity Pathway Analysis., Results: mPIA females showed the least DEGs (0.5% of >22,000 genes) whereas sPIA females had the most (8.6%), indicating a dose-dependent effect. mPIA and sPIA males showed similar changes in gene expression (5.3% and 4.7%, respectively), indicating a threshold effect at mPIA. The pattern of altered genes induced by PIA indicates sex-specific and anemia-dose-dependent effects with increased pro-inflammation in females and decreased neurodevelopment in males., Conclusion: These gene-expression changes may underlie the reduced recognition memory function in male and abnormal social-cognitive behavior in female adult mice following neonatal PIA. These results parallel clinical studies demonstrating sex-specific behavioral outcomes as a function of neonatal anemia., Impact: Phlebotomy-induced anemia (PIA) in neonatal mice results in an altered hippocampal transcriptome and the severity of changes are dependent upon degree of anemia and sex of neonatal mice. The reported findings provide context to the sex-specific outcomes that have been reported in transfusion threshold clinical trials of preterm infants and therefore may inform treatment strategies that may be based on sex. These data advance the field by showing that consequences of PIA may be based in sex-specific transcriptomic alterations. Such changes may also result from other causes of neonatal anemia that also affect term infants., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: Anemia causes blood flow redistribution and altered tissue metabolic behavior to sustain homeostatic oxygen consumption. We hypothesized that anemia severity would correlate with increased regional fractional tissue oxygen extraction among premature neonates., Study Design: Regional oxygen extraction was calculated using pulse oximetry and near-infrared spectroscopy data among neonates <1,250 g during their first 10 postnatal days. Oxygen extraction was assessed for correlations with raw hematocrit levels and following grouping into hematocrit quartiles., Results: Twenty-seven neonates with gestational age 27 ± 2 weeks and birth weight 966 ± 181 g underwent 116 hematocrit determinations. Cerebral and flank oxygen extraction inversely correlated with hematocrit (cerebral r  = -0.527, p  = 0.005; flank r  = -0.485, p  = 0.01). Increased cerebral oxygen extraction was observed for the lowest three hematocrit quartiles (Q1 0.26 ± 0.08, p  = 0.004; Q2 0.24 ± 0.09, p  = 0.01; Q3 0.25 ± 0.09, p  = 0.03; all compared with Q4 0.18 ± 0.10). Increased flank oxygen extraction occurred for the lowest two quartiles (Q1 0.36 ± 0.12, p  < 0.001; Q2 0.35 ± 0.11, p  < 0.001; compared with Q4 0.22 ± 0.13). Splanchnic oxygen extraction demonstrated no similar correlations., Conclusion: Increases in tissue oxygen extraction may indicate early pathophysiologic responses to nascent anemia in premature neonates., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Kidneys are physiologically hypoxic due to huge oxygen consumption for tubular reabsorption. The physiological hypoxia makes the kidney an appropriate organ for sensitively detecting oxygen levels and producing erythropoietin (EPO). In preterm neonates, immature kidneys cannot produce sufficient EPO, which results in anemia of prematurity (AOP). The cause of EPO insufficiency in AOP has been unclear, therefore current therapeutic options are transfusion and injection of recombinant human EPO. This report shows that the cause of insufficient EPO production in AOP is elevated renal oxygen levels due to poor oxygen consumption by immature tubules. Neonatal mice with AOP showed low tubular transporter expression and elevated renal oxygen levels compared with those without AOP. Enhancing transporter expression in AOP mice induced renal hypoxia and EPO production. In preterm neonates, red blood cell counts, hemoglobin levels, and hematocrit levels correlated with tubular function, but not with serum creatinine, gestational age, or birth weight. Furthermore, pharmacological upregulation of hypoxia signaling ameliorated AOP in mice. These data suggest that tubular maturation with increased oxygen consumption is required for renal EPO production.

Objective: The aim of this study is to analyze the relevance of the prenatal and postnatal diagnostic parameters of twin anemia-polycythemia sequence (TAPS)., Methods: Diagnostic data of all cases of TAPS followed in our institution between 2006 and 2013 were reviewed. Statistical analyses were conducted using Bayesian methods., Results: Twenty cases of TAPS were included. We found a relationship between the hemoglobin level and the middle cerebral artery peak systolic velocity (coefficient -0.25 [-0.34, -0.15], Pr(coef < 0) = 99.99%). Sensitivity and specificity of the prenatal diagnosis were 71% and 50%, respectively, regarding the correspondence with postnatal diagnosis. There was no correlation between the number [odds ratio (OR) = 0.89 [0.72, 1.10], Pr(OR > 1) = 14.8%)], the mean diameter (OR = 0.98 [0.32, 3.06], Pr(OR > 1) = 48.9%), or the total diameter (OR = 0.79 [0.36, 1.53], Pr(OR > 1) = 26.3%) of arteriovenous anastomoses and the severity of TAPS., Conclusion: Middle cerebral artery peak systolic velocity is a reliable tool for estimating the hemoglobin level in cases of TAPS. The correspondence between prenatal and postnatal diagnosis is imperfect. Further studies are required to evaluate opportunity of widening postnatal diagnostic criteria. © 2014 John Wiley & Sons, Ltd., (© 2014 John Wiley & Sons, Ltd.)

Background: The aim of red blood cell (RBC) transfusion is to improve tissue oxygenation and relieve anemia-related symptoms in preterm infants. We sought to assess regional cerebral (rSO2 C) and mesenteric (rSO2 M) tissue oxygenation using a near-infrared spectroscopy (NIRS) method and vital signs (heart rate, arterial oxygen saturation, mean arterial blood pressure) in symptomatic preterm infants with anemia who received RBC transfusions., Study Design and Methods: Twenty-three symptomatic patients with anemia who were at least 1 month old, whose gestational age was less than 30 weeks, and whose hematocrit level was not more than 27% were involved in the transfusion group. The control group consisted of preterm infants (Hct ≥ 32) matched for gestational age and postnatal days. The transfusion group was divided into two subgroups based on transfusion duration (2 or 4 hr). Both study groups were monitored for vital signs and rSO2 C, rSO2 M, and mesenteric-cerebral oxygenation ratio (MCOR) via NIRS for 24 hours simultaneously and compared with the control group. NIRS variables and vital signs obtained before, during, and after transfusion were compared both within and between 2- and 4-hour groups., Results: rSO2 C, rSO2 S, and MCOR increased during and after transfusions, while cerebral fractional oxygen extraction (FOEC) and mesenteric fractional oxygen extraction (FOEM) decreased. No significant difference was found between subgroups for NIRS measurements and vital signs. A weak correlation between hemoglobin concentration and FOEC and FOEM was found., Conclusion: RBC transfusion improved cerebral-mesenteric oxygenation and MCOR in symptomatic infants with anemia, independent of the transfusion duration., (© 2013 American Association of Blood Banks.)

Objective: We sought to characterize the effects of "booster" packed red blood cell transfusions on multisite regional oxygen saturation in very low birth weight neonates during the first postnatal week and to examine the utility of fractional tissue oxygen extraction as an estimate of tissue oxygenation adequacy., Study Design: Data were collected in an observational near-infrared spectroscopy (NIRS) pilot survey of 500-1250 g neonates during the first postnatal week. A before-after analysis of "booster" transfusions, defined as empiric 15 mL/kg transfusion following 10 mL/kg cumulative phlebotomy losses, was conducted upon cardiopulmonary, laboratory, and spectroscopy data., Result: Ten neonates (gestational age 26 ± 0 wk; birth weight 879 ± 49 g) received 14 transfusions at 3 ± 0 postnatal days. Mean hematocrit increased from 35.2 ± 1.2 to 38.5 ± 1.2 % (P < 0.05) following transfusion; pH, base deficit, lactate, creatinine, and cardiopulmonary parameters were unchanged. Cerebral, renal, and splanchnic tissue oxygenation increased 10, 18, and 16%, with concomitant decreases in calculated oxygen extraction of 27, 30, and 9% (all P < 0.05), consistent with enhanced tissue oxygenation. These findings were not observed in a non-transfused comparison group of nine patients., Conclusion: "Booster" transfusions improved indices of regional tissue oxygenation while no departures were observed in conventional cardiovascular assessments. We speculate that NIRS-derived oxygenation parameters can provide an objective, graded, and continuous estimate of oxygen delivery-consumption balance not evident using standard monitoring techniques.

Objective: The study investigated the ability of near-infrared spectroscopy (NIRS) to detect subgroups of preterm infants who benefit most from red blood cell (RBC) transfusion in regard to cerebral/renal tissue oxygenation (i) and the number of general oxygen desaturation below 80% (SaO(2) <80%) (ii)., Study Design: Cerebral regional (crSO(2)) and peripheral regional (prSO(2)) NIRS parameters were recorded before, during, immediately after and 24 h after transfusion in 76 infants. Simultaneously, SaO(2) <80% were recorded by pulse oximetry. To answer the basic question of the study, all preterm infants were divided into two subgroups according to their pretransfusion crSO(2) values (<55% and ≥55%). This cutoff was determined by a k-means clustering analysis., Result: crSO(2) and prSO(2) increased significantly in the whole study population. A stronger increase (P<0.0005) of both was found in the subgroup with pretransfusion crSO(2) values <55%. Regarding the whole population, a significant decrease (P<0.05) of episodes with SaO(2) <80% was observed. The subgroup with crSO(2) baselines <55% had significant (P<0.05) more episodes with SaO(2) <80% before transfusion. During and after transfusion, the frequency of episodes with SaO(2) <80% decreased more in this group compared with the group with crSO(2) baselines ≥55%., Conclusion: NIRS measurement is a simple, non-invasive method to monitor regional tissue oxygenation and the efficacy of RBC transfusion. Infants with low initial NIRS values benefited most from blood transfusions regarding SaO(2) <80%, which may be important for their general outcome.

Background: High-dose recombinant human erythropoietin (rEpo) has first been administered in clinical trials for neuroprotection in very preterm neonates at high risk of brain injury and in (near-) term neonates with hypoxic-ischemic encephalopathy. However, recent trials in adults raised concerns about the safety of high-dose rEpo for neuro- and cardioprotection., Objectives: To evaluate the putative accumulation or renal leakage of Epo as a function of developmental stage after repetitive early short-term infusion of high-dose rEpo (3 × 3,000 U/kg within 42 h after birth; NCT00413946) for neuroprotection in very preterm infants., Methods: Epo concentrations were measured using the ELISA technique in the first two consecutive urine specimens after each rEpo infusion., Results: Renal Epo excretion was significantly higher in preterm infants with gestational ages <29 weeks than in more mature infants and reached up to 23% of the administered rEpo within 8 h after each infusion. The urinary Epo concentration did not increase after three repetitive infusions of high-dose rEpo. The ratio of urinary Epo to total protein concentrations was the same in infants with gestational ages <29 weeks and in those with gestational ages ≥29 weeks., Conclusions: Our data suggest that the higher renal Epo excretion in more immature infants may be attributed to a higher glomerular filtration leakage due to the lower maturation of the kidneys and argue against saturation kinetics after multiple doses of 3,000 U/kg rEpo. This information should be considered in future trials on the use of rEpo for neuroprotection in neonates., (Copyright © 2012 S. Karger AG, Basel.)

Objective: To compare transfusion requirements and erythropoietic response in preterms between schedules of rEPO administration once or three times per week, using the same weekly dose., Study Design: Prospective, randomized trial including infants weighing <1500 g at birth and/or were 32 weeks' gestation: Group 1 (60 infants) received subcutaneous rEPO at 250 units kg(-1) per dose, three times weekly for 6 weeks; Group 2 (59 infants), at 750 units kg(-1) per dose, once weekly for 6 weeks. Efficacy was evaluated based on the transfusion requirement, hemoglobin changes, reticulocyte counts, serum transferrin receptor (sTfR) and serum ferritin. The frequency of adverse effects was registered in both groups., Result: A total of 13 infants were transfused in each group (relative risk: 0.98; 95% confidence interval: 0.4 to 2.3). Phlebotomy loss and red blood cell transfusion volumes received were similar in both groups. Hemoglobin levels were lower at end of study in Group 2 (10.6±1.5 g dl(-1) versus 11.5±1.4 g dl(-1); P<0.003). At end of study, reticulocyte counts and sTfR values increased and serum ferritin values decreased, without significant differences between the two groups. Incidence of complications was similar in both groups., Conclusion: The once-weekly rEPO schedule for very low birth weight infants proved as effective as the three-times-weekly schedule, in relation to erythropoietic stimulus and transfusion requirement.

Background: Multiprobe near infrared spectroscopy (NIRS) has been used to study regional cerebral (rSO(2)C), splanchnic (rSO(2)S), and renal (rSO(2)R) tissue oxygenation in newborns. We used this method to study the effects of red blood cell (RBC) transfusions in anemic preterm infants to assess if thresholds for transfusions were appropriate for recognizing a clinical condition permitting tissue oxygenation improvement., Study Design and Methods: Multiprobe NIRS (INVOS 5100, Somanetics) was applied during transfusion to 15 preterm infants with symptomatic anemia of prematurity (hematocrit level of <25%). rSO(2)C, rSO(2)S, and rSO(2)R were recorded at selected times, and then fractional oxygen cerebral extraction ratio [FOEC: (SaO(2)-rSO(2)C)/SaO(2)], fractional oxygen splanchnic extraction ratio [FOES: (SaO(2)-rSO(2)S)/SaO(2)], fractional oxygen renal extraction ratio [FOER: (SaO(2)-rSO(2)R)/SaO(2)], cerebrosplanchnic oxygenation ratio [CSOR: (rSO(2)S/rSO(2)C)], and cerebrorenal oxygenation ratio [CROR: (rSO(2)R/rSO(2)C)] were calculated. In addition, we used Doppler ultrasonography for evaluating cerebral blood flow (CBF), splanchnic blood flow (SBF), and renal blood flow (RBF) velocity., Results: rSO(2)C, rSO(2)S, and rSO(2)R significantly increased during transfusions, while FOEC, FOES, and FOER decreased. CSOR and CROR increased during transfusions. CBF velocity decreased during the study period, while SBF and RBF velocities did not vary., Conclusion: RBC transfusions performed at used thresholds permitted an increase in cerebral, splanchnic, and renal oxygenation. The associated decreases in oxygen tissue extraction might suggest that transfusions were well timed for preventing tissue hypoxia or too early and theoretically prooxidant. Further studies could help to clarify this issue.

Preterm infants often receive multiple packed red blood cell (PRBC) transfusions that are intended to improve tissue oxygen levels. Near-infrared spectroscopy (NIRS) monitors regional cerebral tissue oxygen saturation (CrSO(2)) and splanchnic tissue oxygen saturation (SrSO(2)). Before such technology can be employed in neonatal transfusion management, it must first be established that transfusions result in an increase in tissue oxygen saturation. This prospective, observational study used NIRS to determine if PRBC transfusions increase the CrSO(2) and SrSO(2) of symptomatic anemic premature neonates. CrSO(2) and SrSO(2) values were compared for 20-minute duration immediately before, during, immediately after, and 12 hours after transfusion. As a secondary objective, CrSO(2) and SrSO(2) values were correlated with hemoglobin (Hgb) levels. One-way analysis of variance and Pearson correlation statistical tests were used for analysis. A statistically significant increase in CrSO(2) and SrSO(2) values were observed after transfusion in the 30 subjects included (CrSO(2): 62.8 +/- 1.6, 65.6 +/- 1.7, 68.0 +/- 1.3, 67.6 +/- 1.4, P < 0.001 and SrSO(2): 41.3 +/- 2.2, 46.7 +/- 3.0, 52.1 +/- 2.8, 48.2 +/- 2.5, P < 0.001). No correlation was found between CrSO(2) or SrSO(2) and Hgb values. NIRS identified increases in CrSO(2) and SrSO(2) in preterm neonates after PRBC transfusions and has the potential to become incorporated into neonatal transfusion management paradigms., (Thieme Medical Publishers.)

The regulation of the availability of micronutrients is particularly critical during periods of rapid growth and differentiation such as the fetal and neonatal stages. Both iron deficiency and excess during the early weeks of life can have severe effects on neurodevelopment that may persist into adulthood and may not be corrected by restoration of normal iron levels. This article provides a succinct overview of our current understanding of the extent to which newborns, particularly premature newborns, are able (or not able) to regulate their iron status according to physiologic need. Postnatal development of factors important to iron homeostasis such as intestinal transport, extracellular transport, cellular uptake and storage, intracellular regulation, and systemic control are examined. Also reviewed are how factors peculiar to the sick and premature neonate can further adversely influence iron homeostasis and exacerbate iron-induced oxidative stress, predispose the infant to bacterial infections, and, thus, compromise his or her clinical situation further. The article concludes with a discussion of the areas of relative ignorance that require urgent investigation to rectify our lack of understanding of iron homeostasis in what is a critical stage of development.

Human recombinant erythropoietin has been studied extensively as treatment for a variety of anemias. Since in vitro studies showed the primary etiology of the anemia of prematurity to be insufficient serum erythropoietin concentrations, clinical trials have evaluated the administration of human recombinant erythropoietin to preterm infants to treat this indication. These studies were followed by pharmacokinetic determinations in animal models and preterm infants, which revealed that preterm infants required greater doses of human recombinant erythropoietin because of a more rapid clearance and greater volume of distribution. Recent studies have focused on the administration of human recombinant erythropoietin in the first weeks of life to alleviate the anemia caused by excessive phlebotomy losses, and to prevent the anemia of prematurity. In addition, human recombinant erythropoietin has been tried clinically in a variety of neonatal populations in an attempt to decrease or eliminate transfusions. Although much information has been accumulated about the clinical use of human recombinant erythropoietin in preterm infants over the last 15 years, many questions remain unanswered. The evolution of clinical practice in the care of extremely low birthweight infants continues to affect the number of transfusions. It is likely that human recombinant erythropoietin administration in combination with instituting rigorous transfusion guidelines and decreasing phlebotomy losses will have the greatest impact in decreasing transfusion requirements in all preterm and term neonates, regardless of the etiology of their anemia.

The effect of recombinant human (r-Hu) erythropoietin (Epo) (300 IU/Kg per week for 4 weeks) was studied in healthy preterm infants (n = 14) fed human milk with additional milk protein and high doses of iron. The controls (n = 15) were in themselves a study group and were used to follow the natural course of anaemia of prematurity on such nutrition. Serum immunoreactive Epo (SiEpo) increased significantly 24 h after r-HuEpo injections (range 36 to > 128 mU/ml) and remained at these levels throughout the treatment period. r-HuEpo in such moderate doses kept haemoglobin above 11 g/dl. Bodyweight gain, protein and iron parameters indicated adequacy of dietary protein and iron. In controls, siEpo increased during the first weeks after nutritional supplementation, with a concommitant rise in reticulocyte count. At age 3 weeks, despite low siEpo levels, reticulocyte counts indicated active erythropoiesis. Following further moderate increases in siEpo, the reticulocyte count increased to high levels (7%). The reticulocyte response suggests that erythropoiesis in preterm infants is less dependent upon Epo levels than in adults.

We determined the effects of anemia of prematurity on myocardial, metabolic, and erythropoietic functions. Twelve anemic (hemoglobin range, 65 to 78 gm/L) infants without symptoms (gestational age, (mean +/- SD) 28 +/- 2 weeks; birth weight, 1178 +/- 326 gm) were studied at a postconceptional age of 35 +/- 1.6 weeks. All measurements were done before and 36 to 48 hours after a transfusion of packed erythrocytes. Cardiac output, heart rate, and myocardial function were assessed. Oxygen consumption, carbon dioxide production, resting energy expenditure, arterial oxygen pressure for 50% hemoglobin saturation, and the concentrations of erythropoietin and 2,3-diphosphoglycerate were also determined. After transfusion, increased hemoglobin level (75 +/- 4 to 150 +/- 16 gm/L) and decreased oxyhemoglobin affinity (20.8 +/- 1.7 to 23.6 +/- 2.1 gm/L; p < 0.05) caused a decrease in plasma erythropoietin concentration (from 21.1 +/- 6.2 to 5.8 +/- 1.5 mU/ml; p < 0.01). There was a decrease in heart rate (from 155 +/- 10 beats/min to 146 +/- 7 beats/min) and cardiac output (from 281 +/- 73 ml/kg per minute to 199 +/- 62 ml/kg per minute; p < 0.05). Myocardial function indexes, weight gain, and metabolic demands were normal before and after transfusion. These results suggest that oxygenation is adequately maintained in symptom-free infants with anemia of prematurity.

Recombinant human erythropoietin (rHuEPO) was administered subcutaneously three times a week to 18 infants with the anaemia of prematurity at doses of 75, 150, 300, or 600 units/kg per week for 4 weeks, starting at 3-4 weeks of postnatal age. A significant and dose-dependent increase in reticulocyte count was observed from a mean baseline value of 71 x 10(9)/l to 200 x 10(9)/l after 3 weeks of therapy, compared with a change from 69 to 97 x 10(9)/l in 66 historical controls. The haematocrit value remained unchanged during rHuEPO treatment, whereas it steadily declined until 9 weeks of postnatal age in the controls. These effects were accompanied by a marked reduction in serum iron concentration and transferrin saturation in patients receiving standard-dose iron supplements, but not in those given larger doses. Only 3 of 18 patients required a red blood cell transfusion. These infants were among the most anaemic at entry into the study and 2 of them were unable to complete rHuEPO therapy, while the third developed iron deficiency anaemia. These data indicate that rHuEPO with appropriate iron supplementation may accelerate the recovery from anaemia of prematurity. Larger scale placebo-controlled studies are now needed to confirm these findings and verify their impact on transfusion requirements of premature infants.

A rightward shift in the blood oxygen dissociation curve occurs during the 1st mo of canine life. A detailed peptide analysis indicated that dogs do not have a separate fetal hemoglobin. Other erythrocyte components such as ATP, K+, Na+, and H+ were excluded as significant mediators of the postnatal oxygen affinity change. Erythrocyte 2,3-DPG levels essentially zero in fetal dogs, increased rapidly during the 1st mo of canine life. There was a significant correlation between this postnatal 2,3-DPG increase and the postnatal decrease in blood oxygen affinity. Dialyzed hemolysates of fetal or adult canine blood have the same intrinsic oxygen affinity and the same response to normal adult levels of 2,3-DPG. Furthermore, the magnitude and direction of this 2,3-DPG-induced decrease in oxygen affinity in vitro are comparable to the in vivo postnatal change in oxygen affinity.

The amount of iron in a 1.0 kg preterm infant at birth is sufficient to synthesise only about 18.0 grams of haemoglobin. Since breast milk contains only 40 microgramsFe/100 ml, anaemia will develop in a premature baby fed breast milk unless supplementary iron is given. Preterm infants fed on breast milk are in negative iron balance averaging -0.24 mg/kg X day for at least thirty days after birth, and it can be estimated that they require an intake of about 0.6 mg/kg X day to compensate for obligatory intestinal iron losses. Insensible skin losses, estimated from measurements in adults, are small--of the order of 0.02 micrograms/kg X day, but losses due to venesection may be considerable since each gram of haemoglobin contains 3.4 mg of iron. Absorption of supplementary iron by preterm infants is a linear function of intake, which suggests immature control of iron absorption. Giving blood transfusions seem to diminish iron absorption but may not prevent it altogether. Giving repeated blood transfusions results in high serum ferritin levels similar to those seen in iron overload--however these levels decline spontaneously with age. Preterm infants who are given repeated transfusions do not require iron supplements until the transfusions cease.