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Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The Institutional Review Boards of Intermountain Health (#1051706) and Dell Children’s Medical Center (#00005232) approved the study protocol, and written informed consent was given by parents. All study activities were performed in accordance with institution IRB and privacy guidelines and regulations.

Red blood cell transfusions can be lifesaving for neonates with severe anemia or acute massive hemorrhage. However, it is imperative to understand that red cell transfusions convey unique and significant risks for neonates. The extremely rare risks of transmitting a viral, bacterial, or other microbial infection, or causing circulatory overload are well known and are part of blood transfusion informed consent. Less well known, and not always part of the consent process, are more common risks of transfusing the smallest and most immature NICU patients; specifically, multiple transfusions may worsen inflammatory conditions (particularly pulmonary inflammation), and in certain subsets are associated with retinopathy of prematurity and neurodevelopmental delay. Instituting non-pharmacological transfusion-avoidance techniques reduces transfusion rates. Pharmacological transfusion-avoidance, specifically erythropoietic stimulating agents, further reduces the risk of needing a transfusion. The protocols described herein constitute an efficient and cost-effective transfusion-avoidance program. Using these protocols, many NICU patients can remain transfusion-free., Competing Interests: Declaration of competing interest The authors have no conflicting interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hemolysis is a pathological shortening of the red blood cell lifespan. When hemolysis occurs in a neonate, hazardous hyperbilirubinemia and severe anemia could result. Hemolysis can be diagnosed, and its severity quantified, by the non-invasive measurement of carbon monoxide (CO) in exhaled breath. The point-of-care measurement is called "End-tidal CO corrected for ambient CO" (ETCOc). Herein we explain how ETCOc measurements can be used to diagnose and manage various perinatal/neonatal hemolytic disorders. We provide information regarding five clinical situations; 1) facilitating a precise diagnosis among neonates presenting with anemia or jaundice of unknown etiology, 2) monitoring fetal hemolysis with serial measurements of mothers during pregnancy, 3) measuring the duration of hemolysis in neonates with hemolytic disease, 4) measuring neonates who require phototherapy, to determine whether they have hemolytic vs. non-hemolytic jaundice, and 5) measuring all neonates in the birth hospital as part of a jaundice-detection and management program., Competing Interests: Declaration of competing interest The authors have no conflicting interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

ELGANs (Extremely-Low-Gestational-Age Neonates; those born before 28 weeks gestation) are at risk for developing significant morbidities including retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and cognitive impairment. The pathogenesis of each of these morbidities is complex, but a growing literature suggests that repeated transfusions of adult donor red blood cells (RBC) conveys a propensity to develop these disorders. The biological rationale for the propensities might vary with each morbidity. For instance, hemoglobin A in adult red cells increases oxygen delivery to the developing retina, potentiating ROP, while a proinflammatory nature of adult donor RBC might potentiate BPD. It is possible that fetal RBC harvested from otherwise discarded umbilical cord blood after healthy term births would be a more physiologically appropriate transfusion product for anemic ELGANs. Such a product might result in a lower incidence or severity of the common morbidities. Herein we review our progress, and that of others, toward testing that theory., Competing Interests: Declaration of competing interest The authors have no conflicting interests to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: We previously reported the possible pathogenic role, among infants born ≤29 weeks, of transfusions in bronchopulmonary dysplasia. The present study examined this association in infants born >31 weeks., Study Design: Analysis of red blood cell (RBC) and platelet transfusions in five NICUs to infants born >31 weeks, and chronic neonatal lung disease (CNLD) at six-weeks of age., Results: Seven-hundred-fifty-one infants born >31 weeks were still in the NICU when six-weeks of age. CNLD was identified in 397 (53%). RBC and platelet transfusions were independently associated with CNLD after controlling for potential confounders. For every transfusion, the adjusted odds of developing CNLD increased by a factor of 1.64 (95% CI, 1.38-2.02; p < 0.001)., Conclusions: Among NICU patients born >31 weeks, transfusions received by six weeks are associated with CNLD incidence and severity. Though we controlled for known confounding variables in our regression models, severity of illness is an important confounder that limits our conclusions., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Platelet transfusions are life-saving treatments for specific populations of neonates. However, recent evidence indicates that liberal prophylactic platelet transfusion practices cause harm to premature neonates. New efforts to better balance benefits and risks are leading to the adoption of more restrictive platelet transfusion guidelines in neonatal intensive care units (NICU). Although restrictive guidelines have the potential to improve outcomes, implementation barriers exist. We postulate that as neonatologists become more familiar with the data on the harm of liberal platelet transfusions, enthusiasm for restrictive guidelines will increase and barriers to implementation will decrease. Thus, we focused this educational review on; (1) the adverse effects of platelet transfusions to neonates, (2) awareness of platelet transfusion "refractoriness" in thrombocytopenic neonates and its association with poor outcomes, and (3) the impetus to find alternatives to transfusing platelets from adult donors to NICU patients., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To determine whether premature infants with prostaglandin (PGE)-dependent congenital heart disease (CHD) have impaired cerebral and splanchnic oxygenation (rSO 2 ) using near infrared spectroscopy (NIRS)., Study Design: Cerebral and splanchnic rSO 2 were monitored using NIRS for 48 hours in premature infants <36 weeks gestational age with PGE-dependent CHD and control infants (no CHD or patent ductus arteriosus). Both groups were receiving gavage enteral feedings and were >14 days of life. Mixed effects model estimated the effect of CHD and feedings on splanchnic and cerebral NIRS and accounted for multiple measurements on the same participant at 3 different times around feedings (30 minutes before, during, and 30 minutes after feedings)., Results: Twenty-four participants were enrolled in the study (10 with CHD and 14 controls). The final dataset included 897 measurements from 23 participants. The median gestational age and birthweight were comparable between case and control groups (34 vs 33 weeks gestational age; mean birthweight of 1811 g vs 1820 g, respectively). On average, cerebral NIRS measurements were 9.5 points higher in controls than cases ( P  = .003); and splanchnic NIRS measurements were 13.1 points higher in controls than cases ( P  = .001). The mean cerebral NIRS measurements at baseline, during feeding, and after feeding were 64.0 ± 10.4, 64.5 ± 9.9, and 64.2 ± 9.9 in cases, respectively; and 73.3 ± 6.9, 73.1 ± 6.8, 73.5 ± 6.9 in controls, respectively. The mean splanchnic NIRS measurements at baseline, during feeding, and after feeding were 34.4 ± 15.8, 37.2 ± 14.8, and 38.3 ± 16.1 in cases, respectively; and 50.7 ± 11.0, 51.6 ± 11.1, 50.6 ± 13.5 in controls, respectively., Conclusions: These results demonstrate significantly lower cerebral and splanchnic rSO 2 in premature infants with PGE-dependent CHD compared with control infants. These data raise concerns regarding how unrepaired cyanotic CHD can limit systemic oxygenated blood flow chronically, directly contributing to cerebral and gastrointestinal hypoperfusion and ischemia, ultimately increasing the risk for poor neurodevelopmental outcomes and necrotizing enterocolitis in these premature infants., Competing Interests: The authors declare no conflicts of interest., (© 2024 Published by Elsevier Inc.)

Background and Objectives: Despite advances in the prevention of rhesus (Rh)(D) alloimmunization, alloantibodies to Rh(D) and non-Rh(D) red blood cell antigens continue to be detected in ∼4% of US pregnancies and can result in hemolytic disease of the fetus and newborn (HDFN). Recent reports on HDFN lack granularity and are unable to provide antibody-specific outcomes. The objective of this study was to calculate the frequency of alloimmunization in our large hospital system and summarize the outcomes based on antibody specificity, titer, and other clinical factors., Methods: We identified all births in a 6-year period after a positive red blood cell antibody screen result during pregnancy and summarized their characteristics and outcomes., Results: A total of 707 neonates were born after a positive maternal antibody screen result (3.0/1000 live births). In 31 (4%), the positive screen result was due to rhesus immune globulin alone. Of the 676 neonates exposed to alloantibodies, the direct antibody test (DAT) result was positive, showing antigen-positivity and evidence of HDFN in 37% of those tested. Neonatal disease was most severe with DAT-positive anti-Rh antibodies (c, C, D, e, E). All neonatal red blood cell transfusions (15) and exchange transfusions (6) were due to anti-Rh alloimmunization. No neonates born to mothers with anti-M, anti-S, anti-Duffy, anti-Kidd A, or anti-Lewis required NICU admission for hyperbilirubinemia or transfusion., Conclusions: Alloimmunization to Rh-group antibodies continues to cause a majority of the severe HDFN cases in our hospital system. In neonates born to alloimmunized mothers, a positive DAT result revealing antigen-positivity is the best predictor of anemia and hyperbilirubinemia., (Copyright © 2024 by the American Academy of Pediatrics.)

Objectives: To assess the feasibility of drawing, processing, safety-testing, and banking term umbilical cord blood to meet the packed red blood cell transfusion (RBC Tx) needs of extremely-low-gestational-age neonates (ELGANs)., Design: (1) Retrospectively analyze all ELGANs RBC Tx over the past three years, (2) Estimate local cord blood availability, (3) Assess interest in this project, and implementation barriers, through stakeholder surveys., Results: In three years we cared for 266 ELGANs; 165 (62%) received ≥1 RBC Tx. Annual RBC Tx averaged 197 (95% CI, 152-243). If 10% of our 10,353 annual term births had cord blood drawn and processed, and half of those tested were acceptable for Tx, collections would exceed the 95th % upper estimate for need by >four-fold. Interest exceeded 97%. Identified barriers included FDA approval, training to collect cord blood, and cost., Conclusion: RBC Tx needs of ELGANS could be met by local cord blood collection., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

A transfusion-requiring "late anemia" can complicate the management of neonates convalescing from hemolytic disease of the fetus and newborn (HDFN). This anemia can occur in any neonate after HDFN but is particularly prominent in those who received intrauterine transfusions and/or double-volume exchange transfusions. Various reports describe this condition as occurring based on ongoing hemolysis, either due to passive transfer of alloantibody through breast milk or persistence of antibody not removed by exchange transfusion. However, other reports describe this condition as the result of inadequate erythrocyte production. Both hypotheses might have merit, because perhaps; (1) some cases are primarily due to continued hemolysis, (2) others are primarily hypoproductive, and (3) yet others result from a mixture of these two mechanisms. We propose prospective collaborative studies that will resolve this issue by serially quantifying end-tidal carbon monoxide. Doing this will better inform the assessment and treatment of neonates recovering from HDFN., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: A few patients in neonatal intensive care units (NICU) receive numerous platelet transfusions. These patients can become refractory, defined as transfusions of ≥10 mL/kg failing to increase the platelet count by at least 5,000/µL. Causes of, and best treatments for, platelet transfusion refractoriness in neonates have not been defined., Study Design: Multi-NICU multiyear retrospective analysis of neonates receiving >25 platelet transfusions., Results: Eight neonates received 29 to 52 platelet transfusions. All eight were blood group O. Five had sepsis, four were very small for gestational age, four had bowel resections, two Noonan syndrome, two had cytomegalovirus infection. All eight had some (19-73%) refractory transfusions. Many (2-69%) of the transfusions were ordered when the platelet count was >50,000/µL. Higher posttransfusion counts occurred after ABO-identical transfusions ( p  = 0.026). Three of the eight had late NICU deaths related to respiratory failure; all five survivors had severe bronchopulmonary dysplasia requiring tracheostomy for prolonged ventilator management., Conclusion: Neonates who are high users of platelet transfusions appear to be at high risk for poor outcomes, especially respiratory failure. Future studies will examine whether group O neonates are more likely to develop refractoriness and whether certain neonates would have a higher magnitude of posttransfusion rise if they received ABO-identical donor platelets., Key Points: · Many of the platelet transfusions given in the NICU are given to a small subset of patients.. · Refractoriness to platelet transfusions is common among these very high recipients.. · Neonates who are high users of platelet transfusions appear to be at high risk for poor outcomes.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To evaluate whether transfusions in infants born preterm contribute to the pathogenesis of bronchopulmonary dysplasia (BPD)., Study Design: We conducted a multihospital, retrospective study seeking associations between red blood cell or platelet transfusions and BPD. We tabulated all transfusions administered from January 2018 through December 2022 to infants born ≤29 weeks or <1000 g until 36 weeks postmenstrual age and compared those with BPD grade. We performed a sensitivity analysis to assess the possibility of a causal relationship. We then determined whether each transfusion was compliant with restrictive guidelines, and we estimated effects fewer transfusions might have on future BPD incidence., Results: Eighty-four infants did not develop BPD and 595 did; 352 developed grade 1 (mild), 193 grade 2 (moderate), and 50 grade 3 (severe). Transfusions were given at <36 weeks to 7% of those who did not develop BPD, 46% who did, and 98% who developed severe BPD. For every transfusion the odds of developing BPD increased by a factor of 2.27 (95% CI, 1.59-3.68; P < .001). Sensitivity analyses suggested that transfusions might contribute to BPD. Fifty-seven percent of red blood cell transfusions and 68% of platelet transfusions were noncompliant with new restrictive guidelines. Modeling predicted that complying with restrictive guidelines could reduce the transfusion rate by 20%-30% and the moderate to severe BPD rate by ∼4%-6%., Conclusions: Transfusions were associated with BPD incidence and severity. Lowering transfusion rates to comply with current restrictive guidelines might result in a small but meaningful reduction in BPD rates., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Hemolytic disease of the fetus and newborn (HDFN) can occur when a pregnant woman has antibody directed against an erythrocyte surface antigen expressed by her fetus. This alloimmune disorder is restricted to situations where transplacental transfer of maternal antibody to the fetus occurs, and binds to fetal erythrocytes, and significantly shortens the red cell lifespan. The pathogenesis of HDFN involves maternal sensitization to erythrocyte "non-self" antigens (those she does not express). Exposure of a woman to a non-self-erythrocyte antigen principally occurs through either a blood transfusion or a pregnancy where paternally derived erythrocyte antigens, expressed by her fetus, enter her circulation, and are immunologically recognized as foreign. This review focuses on the genetics, structure, and function of the erythrocyte antigens that are most frequently involved in the pathogenesis of alloimmune HDFN. By providing this information we aim to convey useful insights to clinicians caring for patients with this condition., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Identifying "gold standard" diagnostic tests can promote evidence-based neonatology practice. Hemolysis is a pathological shortening of the erythrocyte lifespan, differing from erythrocyte senescence in responsible mechanisms and clinical implications. Diagnosing hemolysis goes beyond a binary (yes vs. no) determination. It is characterized according to magnitude, and as acute vs. chronic, and genetically based vs. not. For neonates with significant hyperbilirubinemia or anemia, detecting hemolysis and quantifying its magnitude provides diagnostic clarity. The 2022 American Academy of Pediatrics (AAP) Clinical Practice Guideline on management of hyperbilirubinemia in the newborn states that hemolysis is a risk factor for developing significant hyperbilirubinemia and neurotoxicity. The guideline recommends identifying hemolysis from any cause, but specific guidance is not provided. A spectrum of laboratory tests has been endorsed as diagnostic methods for hemolysis. Herein we examine these laboratory tests and recommend one as the "gold standard" for diagnosing and quantifying hemolysis in neonates and infants., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: To understand better those factors relevant to the increment of rise in platelet count following a platelet transfusion among thrombocytopenic neonates., Study Design: We reviewed all platelet transfusions over 6 years in our multi-neonatal intensive care unit system. For every platelet transfusion in 8 neonatal centers we recorded: (1) platelet count before and after transfusion; (2) time between completing the transfusion and follow-up count; (3) transfusion volume (mL/kg); (4) platelet storage time; (5) sex and age of platelet donor; (6) gestational age at birth and postnatal age at transfusion; and magnitude of rise as related to (7) pre-transfusion platelet count, (8) method of enhancing transfusion safety (irradiation vs pathogen reduction), (9) cause of thrombocytopenia, and (10) donor/recipient ABO group., Results: We evaluated 1797 platelet transfusions administered to 605 neonates (median one/recipient, mean 3, and range 1-52). The increment was not associated with gestational age at birth, postnatal age at transfusion, or donor sex or age. The rise was marginally lower: (1) with consumptive vs hypoproductive thrombocytopenia (P < .001); (2) after pathogen reduction (P < .01); (3) after transfusing platelets with a longer storage time (P < .001); and (4) among group O neonates receiving platelets from non-group O donors (P < .001). Eighty-seven neonates had severe thrombocytopenia (<20 000/μL). Among these infants, poor increments and death were associated with the cause of the thrombocytopenia., Conclusion: The magnitude of post-transfusion rise was unaffected by most variables we studied. However, the increment was lower in neonates with consumptive thrombocytopenia, after pathogen reduction, with longer platelet storage times, and when not ABO matched., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To compare serum ferritin and RET-He values among extremely low gestational age neonates ELGANs with other markers of iron-deficient erythropoiesis., Study Design: This is a secondary analysis of the NICHD Darbepoetin Trial. Study data from placebo recipients who had a serum ferritin, a RET-He, and a mean corpuscular volume (MCV) measurement within a 24-hour period were analyzed for correlation., Results: Mixed linear regression models showed no association between ferritin and RET-He at both early (β = 0.0016, p = 0.40) and late (β = -0.0001, p = 0.96) time points. Positive associations were observed between RET-He and MCV at baseline, early, and late time points (p < 0.01, =0.01, <0.001, respectively), while ferritin was not associated with MCV at any time point., Conclusions: Our study shows that RET-He is better correlated with MCV as a marker of iron-limited erythropoiesis than ferritin. The results suggest that ferritin is limited as a marker of iron sufficiency in premature infants., Study Identification: FDA IND Number 100138; ClinicalTrials.gov number NCT03169881; NRN ID number NICHD-NRN-0058 (Darbe)., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Historically, blood for admission laboratory studies in neonates was obtained through direct neonatal phlebotomy. Over the past decade there has been an increase in studies evaluating the validity and clinical impact of using a cord blood sample for many admission laboratory studies. This article reviews various studies that together have shown that using cord blood samples for admission testing in neonates is both acceptable and beneficial., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: It is controversial whether the sex or age of red blood cell (RBC) donors affects mortality or morbidities of transfused newborn infants. We assessed these issues using a multi-year, multi-hospital database linking specific outcomes of neonatal transfusion recipients with RBC donor sex and age., Study Design and Methods: We performed retrospective analyses of all neonates receiving ≥ one RBC transfusion during a 12-year period in all Intermountain Healthcare hospitals, matching mortality and specific morbidities of each transfusion recipient with the sex and age of each donor., Results: There were 6396 RBC transfusions administered to 2086 infants in 15 hospitals. A total of 825 infants were transfused exclusively with RBC from female donors, 935 infants were transfused exclusively with RBC from male donors, and 326 infants were transfused with RBC from both female and male donors. No differences in baseline characteristics were identified among the three groups. Infants who received blood from both male and female donors had more RBC transfusions (5.3 ± 2.9 transfusions if received both male and female donor blood vs. 2.6 ± 2.2 if received blood from only one sex, mean ± SD, p < .001). We identified no significant differences in mortality or morbidities associated with the sex or the age of blood donors. Similarly, an analysis of matched vs. mismatched donor/recipient sex revealed no associations with death or neonatal morbidities., Conclusion: These data support the practice of transfusing newborn infants with RBC obtained from donors of either sex and regardless of donor age., (© 2023 AABB.)

It is important for clinicians who render neonatal care to precisely and reproducibly diagnose anemia; however, confusion arises from various definitions. For the simplicity and consistency of detection, we advocate defining neonatal anemia as a hemoglobin level or hematocrit below the 5th percentile of the reference population, which is highly dependent on gestational and postnatal ages. Thus, a newborn infant delivered at 24 weeks' gestation will have anemia with a blood hemoglobin concentration much lower than a hemoglobin concentration defining anemia at term. Moreover, a hemoglobin concentration defining anemia at term birth is higher than that defining anemia in the same infant 60 days after birth. Diagnosing neonatal anemia can be evidence-based and consistent by using reference intervals derived from large neonatal databases. To do this, we advocate defining anemia as a hemoglobin level that plots below the 5th percentile lower reference interval, defining moderately severe anemia as a hemoglobin value between the 1st and 5th percentile, and defining severe anemia as a hemoglobin level that plots below the 1st percentile. The information provided in this review can easily be adopted by clinical laboratories and individual neonatal care units, thereby fostering application of these definitions for all infants whose hemoglobin levels are measured. Additional normative values included in this review describing various other erythrocyte metrics can likewise be easily adopted. Doing so will codify and standardize the diagnosis of neonatal anemia and will facilitate identifying the cause of the anemia, thus pointing the way to proper additional diagnostic testing and treatment., (Copyright © 2023 by the American Academy of Pediatrics.)

Objectives: To evaluate whether implementing more restrictive neonatal intensive care unit (NICU) platelet transfusion guidelines following the Platelets for Neonatal Transfusion - Study 2 randomized controlled trial (transfusion threshold changed from 50 000/μL to 25 000/μL for most neonates) was associated with fewer NICU patients receiving a platelet transfusion, without adversely affecting outcomes., Study Design: Multi-NICU retrospective analysis of platelet transfusions, patient characteristics, and outcomes during 3 years before vs 3 years after revising system-wide guidelines., Results: During the first period, 130 neonates received 1 or more platelet transfusions; this fell to 106 during the second. The transfusion rate was 15.9/1000 NICU admissions in the first period vs 12.9 in the second (P = .106). During the second period, a smaller proportion of transfusions was administered when the platelet count was in the 50 000-100 000/μL range (P = .017), and a larger proportion when it was <25 000/μL (P = .083). We also saw a fall in the platelet counts that preceded the order for transfusion from 43 100/μL to 38 000/μL (P = .044). The incidence of adverse outcomes did not change., Conclusions: Changing platelet transfusion guidelines in a multi-NICU network to a more restrictive practice was not associated with a significant reduction in number of neonates receiving a platelet transfusion. The guideline implementation was associated with a reduction in the mean platelet count triggering a transfusion. We speculate that further reductions in platelet transfusions can safely occur with additional education and accountability tracking., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Placental abruption can cause maternal blood loss and maternal anemia. It is less certain whether abruption can cause fetal blood loss and neonatal anemia., Study Design: Retrospective multi-hospital 24-month analysis of women with placental abruption and their neonates., Results: Of 55,111 births, 678 (1.2%) had confirmed abruption; 83% of these neonates (564) had one or more hemoglobins recorded in the first day. Four-hundred-seventy (83.3%) had a normal hemoglobin (≥5th% reference interval) while 94 (16.7%) had anemia, relative risk 3.26 (95% CI, 2.66-4.01) vs. >360,000 neonates from previous reference interval reports. The relative risk of severe anemia (<1st% interval) was 4.96 (3.44-7.16). When the obstetrician identified the abruption as "small" or "marginal" the risk of anemia was insignificant., Conclusions: Most abruptions do not cause neonatal anemia but approximately 16% do. If an abruption is not documented as small, it is important to surveille the neonate for anemia., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: In 2011, we reported 38 neonates with subgaleal hemorrhage (SH), relating an increasing incidence. It is unclear whether the incidence in our hospitals continued to rise and which risk factors and outcomes are associated with this condition., Design: We retrospectively analyzed every recognized case of SH in our hospitals from the end of our previous report (2010) to the present (2022). We redescribed the incidence, scored severity, tabulated blood products transfused, and recorded outcomes., Results: Across 141 months, 191 neonates were diagnosed with SH; 30 after vacuum or forceps. The incidence (one/1815 births) was higher than in our 2011 report (one/7124 births). Also, severe SH (requiring transfusion) was more common (one/10,033 births vs. one/20,950 births previously). Four died (all with severe SH) and 12 had neurodevelopmental impairment., Conclusion: Recognized cases of SH are increasing in our system without a clear explanation. Adverse outcomes are rare but continue to occur., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Nucleated red blood cells (NRBC) are very uncommon in the blood of children and adults, but small numbers are not rare in neonates on the day of birth. Elevated NRBC counts in neonates can be seen following erythropoietin dosing. Limited studies in human neonates suggest the time-interval between erythropoietin dosing and the first appearance of NRBC in the blood (the "NRBC emergence-time") is in excess of 24 hours., Methods: We made serial blood counts (Sysmex veterinary analyzer) on ten newborn lambs; five were dosed with darbepoetin (10 μg/kg), and five were dosed with a vehicle-control to assess the NRBC emergence time under relatively controlled laboratory conditions., Results: The first appearance of NRBC was at 24 h (2757 ± 3210 NRBC/μL vs. 0/μL in controls). Peak was 48-72 h (16,758 ± 8434/μL vs. 0/μL in controls), followed by fewer at 96 hours (7823 ± 7114/μL vs. 0/μL in controls). Similarly, reticulocytes peaked at 48-72 h (113,094 ± 3210/μL vs. 10,790 ± 5449/μL in controls), with no changes in platelets or leukocytes., Conclusion: The NRBC emergence time in newborn lambs is similar to reports from newborn humans. By extrapolation, if a neonate has a high NRBC at birth, the erythropoietic stimulus likely occurred within the interval 24 to perhaps 96+ hours prior to birth., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hemolytic disorders can cause severe morbidity or can be life-threatening. Before the recent development of practical and inexpensive testing for hemolysis by quantifying carbon monoxide in end-tidal breath, some hemolytic disorders in perinatal patients were not detected until severely problematic hyperbilirubinemia and/or anemia occurred. Here we review studies aimed at establishing the normal reference intervals for end tidal breath carbon monoxide (ETCO) in various perinatal populations. We also review reports, and new theories, about using this methodology to diagnose and quantify hemolytic disorders in term and premature neonates, anemic pregnant women, and fetuses in utero. The purposes of making these measurements are to; (1) identify patients who have hemolytic disorders, (2) characterize the severity of the hemolysis in each hemolytic patient, and (3) predict and prevent co-morbidities, thereby improving outcomes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To identify neonates with severe anemia at birth, defined by a hemoglobin or hematocrit value within the first 6 hours after birth that plotted below the 1st percentile according to gestational age. For each patient, we retrospectively determined whether caregivers recognized the anemia within the first 24 hours after birth and the probable cause and outcome of anemia., Study Design: This was a retrospective cohort analysis of Intermountain Healthcare population-based data from neonates born between January 2011 and December 2020 who had a hemoglobin or hematocrit value measured within the first 6 hours after birth below the 1st percentile lower reference interval (hematocrit ∼35% in near-term/term neonates)., Result: Among 299 927 live births, we identified 344 neonates with severe anemia at birth. In 191 of these neonates (55.5%), the anemia was recognized by caregivers during the first 24 hours. Anemia was more likely to be recorded as a problem (85%) if the hemoglobin was ≥2 g/dL below the 1st percentile (P < .001). The lowest hemoglobin values occurred in those in whom hemorrhage was the probable cause (P < .013 vs hemolysis and P < .001 vs hypoproduction, mixed cause, or indeterminant.) Treatment was provided to 39.5%. A retrospective review suggested that mixed mechanisms, particularly hemorrhagic plus hemolytic, occurred more commonly than was recognized at the time of occurrence., Conclusions: Severe anemia at birth often went unrecognized on the first day of life. Algorithm-directed retrospective reviews commonly identified causes that were not listed in the medical record. We postulate that earlier recognition and more accurate diagnoses would be facilitated by an electronic medical record-associated hemoglobin/hematocrit gestational age nomogram., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To investigate associations between nucleated red blood cell (NRBC) count in neonates with hypoxic-ischemic encephalopathy (HIE), acute perinatal sentinel events, and neurodevelopmental outcomes and to examine the mechanism(s) causing elevated counts., Study Design: We included newborn infants with HIE treated with therapeutic hypothermia with ≥3 NRBC counts during their neonatal intensive care unit hospitalization and neurodevelopmental evaluations at a mean of 24 ± 6 months., Results: Ninety-five of 152 infants who met our study criteria (63%) had a normal NRBC count after birth, defined as ≤95th percentile of the upper reference interval, and the other 57 (37%) had an elevated count. Documented sentinel events during labor resulting in emergency delivery (eg, acute abruption) (n = 79) were associated with a normal NRBC count (OR, 257; 95% CI, 33-1988). Of the 152 infants evaluated, 134 (88%) survived to discharge. The odds of surviving were 3-fold greater (OR, 3.0; 95% CI, 1.1-8.3) when the first NRBC count was normal than when it was elevated. Normal counts were moderately predictive of infants without neurodevelopmental impairment at a 2-year evaluation (P < .001). NRBC half-life was longer in infants with an elevated NRBC count compared with those with a normal count (60 hours vs 39 hours; P < .01)., Conclusions: In infants with HIE, a normal NRBC count after birth was associated with acute intrapartum events necessitating emergent delivery. Normal counts were modestly predictive of a better prognosis. We speculate that the elevated NRBC counts at birth resulted from hypoxia that occurred earlier or chronically. Impaired clearance of NRBCs from the blood might be one mechanistic explanation for the high counts., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 6/7  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)., 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of Interest: The author has no conflicts of interest relevant to this article to disclose.

Objectives: We constructed reference intervals for end-tidal carbon monoxide (ETCOc) levels of neonates 28 0/7 to 34 6/7 weeks gestation in order to assess hemolytic rate., Study Design: This is a prospective four-NICU study in Bangkok, Thailand, and Utah, USA., Results: Of 226 attempted measurements, 92% were successful. Values from day 1 through 28 were charted and upper (>95th percentile) reference interval limits calculated. During the entire 28 days, the ETCOc upper reference intervals from babies in Bangkok were higher than those in Utah (p < 0.01). No differences were found due to sex, or earliest vs. latest gestation at birth (both p > 0.1). Similar to term neonates, preterm neonates in Bangkok and Utah had higher ETCOc values during the first 48 h after birth than thereafter (p < 0.01)., Conclusions: Using this methodology, and the reference interval chart, the hemolytic rate of preterm infants ≥28 weeks can be assessed., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: We previously reported fetomaternal hemorrhage (FMH) in 1/9160 births, and only one neonatal death from FMH among 219,853 births. Recent reports indicate FMH is not uncommon among stillbirths. Consequently, we speculated we were missing cases among early neonatal deaths. We began a new FMH initiative to determine the current incidence., Methods: We analyzed births from 2011 to 2020 where FMH was diagnosed. We also evaluated potential cases among neonates receiving an emergent transfusion just after birth, whose mothers were not tested for FMH., Results: Among 297,403 births, 1375 mothers were tested for FMH (1/216 births). Fourteen percent tested positive (1/1599 births). Of those, we found 25 with clinical and laboratory evidence of FMH adversely affecting the neonate. Twenty-one received one or more emergency transfusions on the day of birth; all but two lived. We found 17 others who received an emergency transfusion on the day of birth where FMH was not tested for, but was likely; eight of those died. The 42 severe (proven + probable) cases equate to 1/7081 births. We judged that 10 of the 42 had an acute FMH, and in the others it likely had more than a day before birth., Conclusions: We estimate that we fail to diagnose >40% of our severe FMH cases. Needed improvements include (1) education to request maternal FMH testing when neonates are born anemic, (2) education on false-negative FMH tests, and (3) improved FMH communications between neonatology, obstetrics, and blood bank., (© 2021 AABB.)

Background: Neonatal hypoxia-ischemia encephalopathy (HIE) is the leading cause of neonatal death and poor neurodevelopmental outcomes worldwide. Therapeutic hypothermia (TH), while beneficial, still leaves many HIE treated infants with lifelong disabilities. Furthermore, infants undergoing TH often require treatment for pain and agitation which may lead to further brain injury. For instance, morphine use in animal models has been shown to induce neuronal apoptosis. Dexmedetomidine is a potent α 2 -adrenergic receptor agonist that may be a better alternative to morphine for newborns with HIE treated with TH. Dexmedetomidine provides sedation, analgesia, and prevents shivering but does not suppress ventilation. Importantly, there is increasing evidence that dexmedetomidine has neuroprotective properties. Even though there are limited data on pharmacokinetics (PK), safety and efficacy of dexmedetomidine in infants with HIE, it has been increasingly administered in many centers. Objectives: To review the current approach to treatment of pain, sedation and shivering in infants with HIE undergoing TH, and to describe a new phase II safety and pharmacokinetics randomized controlled trial that proposes the use of dexmedetomidine vs. morphine in this population. Methods: This article presents an overview of the current management of pain and sedation in critically ill infants diagnosed with HIE and undergoing TH for 72 h. The article describes the design and methodology of a randomized, controlled, unmasked multicenter trial of dexmedetomidine vs. morphine administration enrolling 50 (25 per arm) neonates ≥36 weeks of gestation with moderate or severe HIE undergoing TH and that require pain/sedation treatment. Results and Conclusions: Dexmedetomidine may be a better alternative to morphine for the treatment of pain and sedation in newborns with HIE treated with TH. There is increasing evidence that dexmedetomidine has neuroprotective properties in several preclinical studies of injury models including ischemia-reperfusion, inflammation, and traumatic brain injury as well as adult clinical trials of brain trauma. The Dexmedetomidine Use in Infants undergoing Cooling due to Neonatal Encephalopathy (DICE) trial will evaluate whether administration of dexmedetomidine vs. morphine is safe, establish dexmedetomidine optimal dosing by collecting opportunistic PK data, and obtain preliminary neurodevelopmental data to inform a large Phase III efficacy trial with long term neurodevelopment impairment as the primary outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baserga, DuPont, Ostrander, Minton, Sheffield, Balch, Bahr and Watt.)

Objective: To create neonatal reference intervals for the MicroR and HYPO-He complete blood count (CBC) parameters and to test whether these parameters are sensitive early markers of disease at early stages of microcytic/hypochromic disorders while the CBC indices are still normal., Study Design: We retrospectively collected the CBC parameters MicroR and HYPO-He, along with the standard CBC parameters, from infants aged 0-90 days at Intermountain Healthcare hospitals using Sysmex hematology analyzers. We created reference intervals for these parameters by excluding values from neonates with proven microcytic disorders (ie, iron deficiency or alpha thalassemia) from the dataset., Result: From >11 000 CBCs analyzed, we created reference intervals for MicroR and HYPO-He in neonates aged 0-90 days. The upper intervals are considerably higher in neonates than in adults, validating increased anisocytosis and polychromasia among neonates. Overall, 52% of neonates with iron deficiency (defined by reticulocyte hemoglobin equivalent <25 pg) had a MicroR >90% upper interval (relative risk, 4.14; 95% CI, 3.80-4.53; P < .001), and 68% had an HYPO-He >90% upper interval (relative risk, 6.64; 95% CI, 6.03-7.32; P < .001). These 2 new parameters were more sensitive than the red blood cell (RBC) indices (P < .001) in identifying 24 neonates with iron deficiency at birth., Conclusions: We created neonatal reference intervals for MicroR and HYPO-He. Although Sysmex currently designates these as research use only in the US, they can be measured as part of a neonate's CBC with no additional phlebotomy volume or run time and can identify microcytic and hypochromic disorders even when the RBC indices are normal., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In North America, jaundiced neonates are not usually tested for G6PD deficiency if the family is of European ancestry. However, we describe such a family where ≥35 males have had severe (Class I) G6PD deficiency. Many of the jaundiced neonates did not have this diagnosis considered, at least three of whom developed bilirubin neurotoxicity. Over seven generations 35 affected males were identified. Three developed signs of kernicterus spectrum disorder; three had exchange transfusions for hyperbilirubinemia; and nine received one or more blood transfusions during childhood., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To determine, as part of our Utah Newborn Nursery Bilirubin Management Program, whether end-tidal carbon monoxide concentration (ETCOc) measurements in all newborns in our nursery receiving phototherapy were associated with outcomes related to the management of hyperbilirubinemia, including time (hours after birth) when phototherapy was initiated, total duration of phototherapy during the nursery stay, repeat phototherapy treatments, and hospital readmission for phototherapy., Study Design: We performed a planned interim analysis of a component of our program in which we measured ETCOc noninvasively using CoSense on each newborn in our nursery receiving phototherapy and recorded specific outcomes related to phototherapy management., Results: Of 1856 newborns admitted to our nursery in a 6-month period in 2020, 170 (9.8%) were treated with phototherapy. An ETCOc reading was successfully obtained in 145 of 151 attempts (96%). Higher ETCOc values were associated with earlier institution of phototherapy and longer duration of phototherapy. For every 1-ppm increase in ETCOc, phototherapy was started 9 hours earlier (95% CI, 3.3-14.8; P = .002) and was administered for an additional 9.3 hours (95% CI, 4.1-14.6; P < .001). Three newborns were readmitted to the hospital for intensive phototherapy; while in the nursery, all 3 had an elevated ETCOc (2.2, 2.6, and 2.9 ppm)., Conclusions: Our findings provide answers to questions raised in the 2004 American Academy of Pediatrics bilirubin guidelines. In our neonatal nursery, measuring ETCOc in all phototherapy recipients was feasible and safe, and the results were associated with multiple aspects of phototherapy management. Higher ETCOc values predicted earlier and longer phototherapy courses., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In order to reduce iron deficiency in neonates at-risk for iron deficiency, we implemented a guideline to increase the consistency of early iron supplementation in infants of diabetic mothers, small for gestational age neonates and very low birthweight premature neonates. Three years following implementation we performed a retrospective analysis in order to assess adherence to the guideline and to compare timing of early iron supplementation and reticulocyte-hemoglobin (RET-He) values at one month of life in at-risk infants. Adherence with early iron supplementation guidelines was 73.4% (399/543) with 51% (275/543) having RET-He values obtained at one month. Despite good adherence, 16% (44/275) had RET-He <25 pg (5th percentile for gestational age). No infants receiving red blood cell transfusion (0/20) had RET-He <25 pg vs. 26.1% (40/153) of those treated with darbepoetin (p < 0.001). There was no evidence of increased feeding intolerance (episodes of emesis/day) with early iron supplementation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To develop a statistically rigorous, hour-specific bilirubin nomogram for newborns based on a very large data set; and use it prospectively as a replacement for the 1999 Bhutani nomogram., Study Design: This was a retrospective analysis of first total serum bilirubin (TSB) measurements from 15 years of universal bilirubin screening during birth hospitalizations at 20 Intermountain Healthcare hospitals. Hour-specific TSB values were assembled into a nomogram by percentile, and subgroups were compared., Results: The information obtained included robust data in the first 12 hours after birth (which was not included in the 1999 nomogram), general agreement with the 1999 nomogram for values in the first 60 hours, but higher 75th and 95th percentile TSB values thereafter in the new version, no difference in TSB between male and female infants, higher TSB values among earlier gestation neonates (35 0/7 -36 6/7  weeks vs ≥37 weeks, P < .0001), and lower TSB values in neonates of Black race (P < .0001) and higher values in neonates of Asian race (P < .001)., Conclusions: An updated and more informative Bhutani neonatal bilirubin nomogram, based on 140 times the number of subjects included the 1999 version, is now in place in our health care system., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Building on our previous study, showing a correlation between ferritin in serum and urine, we conducted a feasibility evaluation, measuring urinary ferritin as a potential noninvasive screening test for iron deficiency among NICU patients., Study Design: This was a prospective analysis of paired serum/urine ferritin levels. We defined iron-limited erythropoiesis by a RET-He <5th percentile lower reference interval (<28 pg)., Results: We obtained 49 paired serum/urine samples from neonates judged as at-risk for iron deficiency. Urine ferritin ("corrected" for urine creatinine and specific gravity) correlated with serum ferritin (correlation coefficient of log 10 -transformed values 0.44). A corrected urine ferritin <12 ng/mL had a sensitivity of 82% (95% CI, 67-93%) and a specificity of 100% (CI, 66-100%) for detecting iron-limited erythropoiesis, with a positive predictive value of 100% (CI, 89-100%)., Conclusions: Measuring urinary ferritin in NICU patients is feasible. Since low values identify iron-limitation, this could become a useful noninvasive screen.

In a two-part process, we assessed elements of the principal hormonal pathway regulating iron homeostasis in human neonates. Part 1: Quantifying erythropoietin (Epo), erythroferrone (ERFE), hepcidin, and relevant serum and erythrocytic iron-related metrics in umbilical cord blood from term (n = 13) and preterm (n = 10) neonates, and from neonates born to mothers with diabetes and obesity (n = 13); Part 2: Quantifying serum Epo, ERFE, and hepcidin before and following darbepoetin administration. Part 1: We measured Epo, ERFE and hepcidin in all cord blood samples. Epo and ERFE levels did not differ between the three groups. Preterm neonates had the lowest hepcidin levels, while neonates born to diabetic women with a very high BMI had the lowest ferritin and RET-He levels. Part 2: Following darbepoetin dosing, ERFE levels generally increased (p < 0.05) and hepcidin levels generally fell (p < 0.05). Our observations suggest that the Epo/ERFE/hepcidin axis is intact in the newborn period., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The objective of this study is to explore the hypothetical number of neonates where an exchange transfusion (ET) could be prevented by emergency administration of an inhibitor of bilirubin production., Study Design: We identified all neonates who received an ET in our NICUs during the past 12 years. We reviewed the indications for ET and recorded the time between ordering and beginning the exchange., Results: Forty-six neonates underwent ET, 37 (80.4%) for hemolytic hyperbilirubinemia (36.9 ± 2.9 weeks gestation and 2.5 ± 2.1 days old at ET). The mean delay period was 7.5 ± 3.5 h. Nine (19.6%) had ET not involving bilirubin., Conclusions: A trial testing compounds that can inhibit bilirubin production would have about three eligible neonates/years in our system. Since our births are 1% of national, up to 300 neonates/years might qualify for such a study.