Low-Titer Type O Whole Blood for Transfusing Perinatal Patients after Acute Hemorrhage: A Case Series.

Objective Acute and massive blood loss is fortunately a rare occurrence in perinatal/neonatal practice. When it occurs, typical transfusion paradigms utilize sequential administration of blood components. However, an alternative approach, transfusing type O whole blood with low anti-A and anti-B titers, (LTOWB) has recently been approved and utilized in trauma surgery. Study Design Retrospective analysis of all perinatal patients who have received LTOWB after acute massive hemorrhage at the Intermountain Medical Center. Results LTOWB was the initial transfusion product we used to resuscitate/treat 25 women with acute and massive postpartum hemorrhage and five infants with acute hemorrhage in the first hours/days after birth. We encountered no problems obtaining or transfusing this product and we recognized no adverse effects of this treatment. Conclusion Transfusing LTOWB to perinatal patients after acute blood loss is feasible and appears at least as safe a serial component transfusion. Its use has subsequently been expanded to multiple hospitals in our region as first-line transfusion treatment for acute perinatal hemorrhage. Key Points Low-titer type O whole blood (LTOWB) was our initial transfusion product for 30 perinatal patients with acute hemorrhage. Twenty-five of these were obstetrical patients and five were neonatal patients. We encountered no problems with, or adverse effects from LTOWB in any of these patients. LTOWB transfusions to women were ten days since donor draw (interquartile range, 8-13) and to neonates was six days (5-8).

Erythrokinetic mechanism(s) causing the "late anemia" of hemolytic disease of the fetus and newborn.

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.

Can Red Blood Cell and Platelet Transfusions Have a Pathogenic Role in Bronchopulmonary Dysplasia?

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.

Hyperferritinemia among very-low-birthweight infants in Thailand: a prospective cohort study.

OBJECTIVES: To determine the incidence of hyperferritinemia in VLBW infants, and its association with neonatal morbidity. STUDY DESIGN: Prospective cohort study in a tertiary-level hospital in Bangkok, from March 2022 to January 2023. Serum ferritin (SF) was measured in VLBW infants at one month and repeated monthly for those with hyperferritinemia (SF > 300 ng/mL). RESULTS: Gestational age and birth weight were 29.7 ± 2.4 weeks (mean ± SD) and 1100 g (IQR, 830, 1340). Hyperferritinemia was identified in 30.1% (95% CI, 20.8-41.4). After adjustment, only packed red cell transfusion >15 mL/kg was associated with hyperferritinemia (RR 3.1; 95% CI, 1.5-6.4). All elevated SF levels returned to normal within four months. Hyperferritinemia was associated with severe bronchopulmonary dysplasia (RR 2.3, 95% CI, 1.0-5.4) and retinopathy of prematurity (RR 3.5, 95% CI, 1.4-8.6). CONCLUSION: Hyperferritinemia is common among our VLBW infants, particularly after transfusion, and is associated with severe BPD and ROP.

Banked term umbilical cord blood to meet the packed red blood cell transfusion needs of extremely-low-gestational-age neonates: a feasibility analysis.

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.

Alloimmune hemolytic disease of the fetus and newborn: genetics, structure, and function of the commonly involved erythrocyte antigens.

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.

Serum ferritin values in neonates <29 weeks' gestation are highly variable and do not correlate with reticulocyte hemoglobin content.

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 (ß = 0.0016, p = 0.40) and late (ß = -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).

Neonatal Thrombocytopenia: Factors Associated With the Platelet Count Increment Following Platelet Transfusion.

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.

A "Gold Standard" Test for Diagnosing and Quantifying Hemolysis in Neonates and Infants.

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.

Increased blood reactive oxygen species and hepcidin in obstructive sleep apnea precludes expected erythrocytosis.

Obstructive sleep apnea (OSA) causes intermittent hypoxia during sleep. Hypoxia predictably initiates an increase in the blood hemoglobin concentration (Hb); yet in our analysis of 527 patients with OSA, >98% did not have an elevated Hb. To understand why patients with OSA do not develop secondary erythrocytosis due to intermittent hypoxia, we first hypothesized that erythrocytosis occurs in these patients, but is masked by a concomitant increase in plasma volume. However, we excluded that explanation by finding that the red cell mass was normal (measured by radionuclide labeling of erythrocytes and carbon monoxide inhalation). We next studied 45 patients with OSA before and after applying continuous positive airway pressure (CPAP). We found accelerated erythropoiesis in these patients (increased erythropoietin and reticulocytosis), but it was offset by neocytolysis (lysis of erythrocytes newly generated in hypoxia upon return to normoxia). Parameters of neocytolysis included increased reactive oxygen species from expanded reticulocytes' mitochondria. The antioxidant catalase was also downregulated in these cells from hypoxia-stimulated microRNA-21. In addition, inflammation-induced hepcidin limited iron availability for erythropoiesis. After CPAP, some of these intermediaries diminished but Hb did not change. We conclude that in OSA, the absence of significant increase in red cell mass is integral to the pathogenesis, and results from hemolysis via neocytolysis combined with inflammation-mediated suppression of erythropoiesis.

Diagnosing Anemia in Neonates: An Evidence-Based Approach.

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.

Associations between blood donor sex and age, and outcomes of transfused newborn infants.

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.

Neonatal Intensive Care Unit Patients Receiving More Than 25 Platelet Transfusions.

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..

Platelet Transfusions in a Multi-Neonatal Intensive Care Unit Health Care Organization Before and After Publication of the PlaNeT-2 Clinical Trial.

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.

Placental abruption and neonatal anemia.

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.

Nucleated Red Blood Cell Emergence-Time in Newborn Lambs Following a Dose of Darbepoetin Alfa.

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.