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).

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.

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..

An Infant With Hereditary Fructose Intolerance and a Novel Presentation of Disseminated Intravascular Coagulopathy Following Pyloromyotomy.

Hereditary fructose intolerance is a rare autosomal recessive metabolic disorder characterized by liver failure, renal tubulopathy, growth retardation, and occasionally death upon exposure to fructose. We present a 2-month-old male infant diagnosed with pyloric stenosis who developed disseminated intravascular coagulopathy following pyloromyotomy. Unexplained persistent coagulopathy, acute liver failure, and metabolic dysfunction led to whole-exome sequencing, which revealed compound heterozygous variants in ALDOB (p.Arg60Ter and p.Ala150Pro), diagnostic of hereditary fructose intolerance. Shortly after initiating a fructose-free diet, our patient had resolution of his coagulopathy, hepatic, and metabolic dysfunction.

Early iron supplementation and iron sufficiency at one month of age in NICU patients at-risk for iron deficiency.

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.

Is the erythropoietin-erythroferrone-hepcidin axis intact in human neonates?

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.

Urinary ferritin; a potential noninvasive way to screen NICU patients for iron deficiency.

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 log10-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.

Medicinal Uses of Hematopoietic Growth Factors in Neonatal Medicine.

This review focuses on certain hematopoietic growth factors that are used as medications in clinical neonatology. It is important to note at the chapter onset that although all of the pharmacological agents mentioned in this review have been approved by the US Food and Drug administration for use in humans, none have been granted a specific FDA indication for neonates. Thus, in a sense, all of the agents mentioned in this chapter could be considered experimental, when used in neonates. However, a great many of the pharmacological agents utilized routinely in neonatology practice do not have a specific FDA indication for this population of patients. Consequently, many of the agents reviewed in this chapter are considered by some practitioners to be nonexperimental and are used when they judge such use to be "best practice" for the disorders under treatment.The medicinal uses of the agents in this chapter vary considerably, between geographic locations, and sometimes even within an institutions. "Consistent approaches" aimed at using these agents in uniform ways in the practice of neonatology are encouraged. Indeed some healthcare systems, and some individual NICUs, have developed written guidelines for using these agents within the practice group. Some such guidelines are provided in this review. It should be noted that these guidelines, or "consistent approaches," must be viewed as dynamic and changing, requiring adjustment and refinement as additional evidence accrues.

First report of using low-titer cold-stored type O whole blood in massive postpartum hemorrhage.

BACKGROUND: In cases of massive hemorrhage in the US military, improved outcomes have been reported with the use of warm, fresh whole blood transfusions. Cold-stored low-titer type O whole blood (LTOWB) has become the preferred product for resuscitation of severe bleeding in deployed surgical units. Reports of LTOWB use in civilian trauma are becoming more frequent. CASE REPORT: We report our experience with emergency transfusion of LTOWB for a woman with massive postpartum hemorrhage. The patient had two previous cesarean section deliveries at term without complications. With her third elective cesarean section at term, blood loss during surgery was not excessive, but 3 to 4 hours later she had an estimated blood loss of 3600 mL. Despite measures to control the hemorrhage, she rapidly became hypotensive and tachycardic, and our massive transfusion protocol (MTP) was activated. The transfusion service had very recently incorporated LTOWB into Trauma Pack 1 of the MTP. She received two LTOWB units, after which her hemorrhaging ceased, blood pressure normalized, and she became alert. One hour later she received one unit of fresh frozen plasma and one unit of red blood cells (RBCs). The following morning she received one unit of crossmatched RBCs, for a hematocrit of 20.7%. She was discharged home on Day 4, and she remains healthy. CONCLUSIONS: This is the first report of which we are aware of massive postpartum hemorrhage treated using LTOWB. Our positive experience leads us to speculate that this approach could have a role in massive obstetric hemorrhage.

Screening umbilical cord blood for congenital Iron deficiency.

OBJECTIVES: Small for gestational age infants (SGA), infants of diabetic mothers (IDM), and very low birth weight infants (VLBW) are at risk for congenital iron deficiency. We evaluated the iron status of SGA, IDM, and VLBW neonates at birth and sought mechanistic explanations in those with iron deficiency. METHODS: This was a prospective study. If congenital iron deficiency was present, maternal iron studies were obtained. When neonates were two weeks old, their iron status was reevaluated. RESULTS: Sixteen of 180 neonates screened were iron deficient at birth. The Body Mass Index of the 16 mothers was high. These mothers often had mild iron deficiency and measurable hepcidin levels. Two weeks after birth, neonates had improved iron measurements. CONCLUSIONS: Among SGA, IDM, and VLBW neonates, maternal obesity is a risk factor for congenital iron deficiency. We speculate that elevated hepcidin levels in obese pregnant women impede iron absorption and interfere with transplacental iron transfer.

Ferritin in serum and urine: A pilot study.

Serum ferritin reflects total body iron stores, thus a low serum ferritin is used as a parameter of iron deficiency. In healthy adults in Japan, urine ferritin levels were about 5% of serum ferritin levels, with a correlation coefficient of 0.79. It is not known whether a low urine ferritin could serve as a non-invasive screen for iron deficiency. If so, this might be useful for neonates and young children, avoiding phlebotomy to screen for iron deficiency. However, for urinary ferritin screening to be feasible, ferritin must be measurable in the urine and correlate with serum ferritin. Testing should also clarify whether the iron content of ferritin in serum and urine are similar. In this pilot feasibility study we measured ferritin in paired serum and urine samples of healthy adult males, healthy term neonates, growing preterm neonates, and children who had very high serum ferritin levels from liver disorders or iron overload. We detected ferritin in every urine sample, and found a correlation with paired serum ferritin (Spearman correlation coefficient 0.78 of log10-transformed values). These findings suggest merit in further studying urinary ferritin in select populations, as a potential non-invasive screen to assess iron stores.

Non-Immune Hydrops, Hypotonia, Encephalopathy, and Liver Failure with Novel Compound Heterozygous AHCY Mutations.

A late-preterm infant with a prenatal diagnosis of non-immune hydrops was born with hypotonia, poor respiratory effort, chylothorax, encephalopathy, coagulopathy, progressive hepatic failure, and refractory pulmonary hypertension. Life support was withdrawn at 7 days of life due to multisystem organ failure. Rapid whole exome sequencing revealed novel compound heterozygous mutations in the gene encoding S-adenosylhomocysteine hydrolase (AHCY); each novel variant was carried by an asymptomatic parent. Reports of neonates with other AHCY mutations describe a pathology of varying severity. AHCY mutations should be considered when seeking an etiology for neonates with the combination of non-immune hydrops, hypotonia, encephalopathy, and liver failure.

Fetal presentation of congenital dyserythropoietic anemia type 1 with novel compound heterozygous CDAN1 mutations.

The congenital dyserythropoietic anemias are a heterogeneous group of disorders characterized by anemia and ineffective erythropoiesis. Congenital dyserythropoietic anemia type I (CDA1) can present in utero with hydrops fetalis, but more often it presents in childhood or adulthood with moderate macrocytic anemia, jaundice, and progressive iron-overload. CDA1 is inherited in an autosomal recessive manner, with biallelic pathogenic variants in CDAN1 or C15orf41. This case report documents a severe fetal presentation of CDA1 where we identified two novel compound heterozygous mutations in CDAN1 and describes the associated pathologic findings and levels of iron-regulatory proteins hepcidin, erythroferrone, and GDF15.

Anemia, red blood cell transfusions, and necrotizing enterocolitis.

In the past 15 years, multiple clinical studies have identified a temporal association between red blood cell (RBC) transfusions and necrotizing enterocolitis (NEC). With some variability, most of these studies indicate that up to one-third of all cases of NEC involving very low-birth weight infants may occur within 24-48h after receiving a RBC transfusion. There is also evidence that the risk of such transfusion-associated NEC may be higher in infants transfused with the greatest severity of anemia. In this article, we summarize the clinical evidence pertaining to these issues; specifically, the contribution of RBC transfusions, and the contribution of severity of underlying anemia, to the pathogenesis of a type of NEC potentially termed, "transfusion/anemia-associated NEC."

Iron Supplements for Infants at Risk for Iron Deficiency.

Professional societies have published recommendations for iron dosing of preterm neonates, but differences exist between guidelines. To help develop standardized guidelines, we performed a 10-year analysis of iron dosing in groups at risk for iron deficiency: IDM (infants of diabetic mothers), SGA (small for gestational age), and VLBW premature neonates (very low birth weight, <1500 g). We analyzed iron dosing after red cell transfusions and erythropoiesis-stimulating agents (ESA). Of IDM, 11.8% received iron in the hospital; 9.8% of SGA and 27.1% of VLBW neonates received iron. Twenty percent of those who received iron had it started by day 14; 63% by 1 month. Supplemental iron was stopped after red cell transfusions in 73% of neonates receiving iron. An ESA was administered to 1677, of which 33% received iron within 3 days. This marked variation indicates that a consistent approach is needed, and using this report and a literature review, we standardized our iron-dosing guidelines.

Two novel mutations in TMPRSS6 associated with iron-refractory iron deficiency anemia in a mother and child.

In an iron deficient child, oral iron repeatedly failed to improve the condition. Whole exome sequencing identified one previously reported plus two novel mutation in the TMPRSS6 gene, with no mutations in other iron-associated genes. We propose that these mutations result in a novel variety of iron-refractory iron deficiency anemia.