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.

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.

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.

Severe Anemia at Birth-Incidence and Implications.

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.

Implications of an Elevated Nucleated Red Blood Cell Count in Neonates with Moderate to Severe Hypoxic-Ischemic Encephalopathy.

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.

Neonatal Reference Intervals for the Complete Blood Count Parameters MicroR and HYPO-He: Sensitivity Beyond the Red Cell Indices for Identifying Microcytic and Hypochromic Disorders.

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.

Improvement Initiative: End-Tidal Carbon Monoxide Measurement in Newborns Receiving Phototherapy.

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.

A New Hour-Specific Serum Bilirubin Nomogram for Neonates ≥35 Weeks of Gestation.

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 (350/7-366/7 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.

Decision Accuracy and Safety of Transcutaneous Bilirubin Screening at Intermountain Healthcare.

OBJECTIVE: To quantify the risk that transcutaneous bilirubin (TcB) screening would fail to recommend phototherapy for a neonate who would have qualified for it if total serum bilirubin (TSB) screening were used. STUDY DESIGN: We conducted a quality improvement project where simultaneous TcB and TSB were obtained on neonates ≥35 weeks of gestation during birth hospitalizations in our hospital system. Using our Utah bilirubin management algorithm, we quantified the risk that TcB screening would fail to identify the need for a confirmatory TSB when TSB screening alone would have revealed that phototherapy was indicated. RESULTS: In 3 hospitals, we obtained 727 paired TcB/TSB measurements. Two instances utilized a blood gas radiometer for TSB, and 725 utilized the clinical laboratory-based TSB method. One of the 727 instances had a TcB indicating NO PHOTOTHERAPY, when the simultaneous TSB indicated PHOTOTHERAPY NEEDED. The TSB from that instance was 1 of the 2 from the blood gas radiometer. We estimate the risk of such an error occurring is 1.4 per 1000 TcB measurements (95% CI 0.03-7.6 per 1000). When only the laboratory TSB is used, we estimate the risk of such an error occurring to be 0 per 1000 TcB measurements (95% CI 0.0-5.1 per 1000). CONCLUSIONS: Using TcB for screening at the birth hospital can identify those qualifying for phototherapy, using the Utah guidelines, with 1 of 727 neonates with a blood gas bilirubin and none of 725 with a laboratory-based analysis misidentified as not needing phototherapy when by TSB they did.

Early Hyperbilirubinemia in Neonates with Down Syndrome.

OBJECTIVE: To compare total serum bilirubin (TSB) levels, phototherapy usage, and hospital readmission for jaundice among neonates with Down syndrome vs controls. STUDY DESIGN: A retrospective cohort study using 15 years of multihospital data. We created control reference intervals (5th, median, and 95th percentiles) for initial TSB values hourly during the first days after birth, and determined the proportion of neonates with Down syndrome whose TSB exceeded the 95th percentile control interval. We determined the proportion with an initial TSB exceeding the upper control reference interval, the highest TSB recorded, the percentage of neonates receiving phototherapy, and the rate of hospital readmission for jaundice treatment. RESULTS: We compared 357 neonates with Down syndrome with 377 368 controls. Compared with controls, those with Down syndrome had 4.7 times the risk (95% CI, 3.9-5.7; P < .0001) of an initial TSB exceeding the 95th percentile control interval (23.5% vs 5.0%), 8.9 times (95% CI, 8.1-9.8; P < .0001) the phototherapy usage (62.2% vs 7.0%), and 3.6 times (95% CI, 1.6-8.2; P = .0075) the readmission rate for jaundice (17.4 vs 4.8 per 1000 live births). CONCLUSIONS: Neonates with Down syndrome have a substantial risk of early hyperbilirubinemia. The American Academy of Pediatrics currently advises obtaining an early screening complete blood count from neonates with Down syndrome. We submit that assessing their TSB is also advisable.

Six children with pyruvate kinase deficiency from one small town: molecular characterization of the PK-LR gene.

We identified the pyruvate kinase liver/red cell enzyme gene mutation of 8 children previously diagnosed with pyruvate kinase deficiency who were living in a remote town in the western United States. Six were found to be homozygous for the mutation 1529G-A (510 Arg-Gln). Two previously thought to have pyruvate kinase deficiency did not, because they were heterozygous.

Tolerance of an enterally administered simulated amniotic fluid-like solution by neonates recovering from surgery for congenital bowel abnormalities.

OBJECTIVE: We report a single-centered, Phase I pilot trial, testing the enteral administration of an experimental amniotic fluid-like solution to 10 neonates who were otherwise "NPO" following surgery for congenital bowel abnormalities. The overall hypothesis was that the trophic effect of the solution on intestinal villi would facilitate advancement to full enteral feedings. The specific hypothesis tested in this pilot trial was that the solution would be tolerated. STUDY DESIGN: Ten neonates who were NPO following surgery for congenital bowel abnormalities, were studied before any "trophic" feedings were begun. Each received an experimental, sterile, isotonic, amniotic fluid-like solution at a dose of 20 ml/kg/day enterally. When milk feedings were begun they were mixed with the experimental solution. Increases in the volume of milk feedings occurred at the discretion of the neonatologist and surgeon, and the experimental solution was discontinued any time the neonatologist or surgeon felt it was not tolerated, or when 100 ml of milk feedings/kg/day was achieved. We quantified the amount and character of emesis, stools, and gastric residuals, measured abdominal girth and blood pressure, looked for skin rashes, and sought any signs of intolerance or adverse events. We recorded the days to achieve milk feedings of 20, 50, 100, and 120 ml/kg/day and length of hospital stay. RESULTS: The experimental solution was begun 4 to 32 days after surgery, invariably prior to the institution of "trophic" milk feedings. All subjects completed the doses with no evidence of intolerance. All achieved 100 ml/kg of milk feedings 14 days, or fewer, following institution of the experimental solution (mean 11.1 days, range, 3 to 14). All lived and were discharged home 20.2 days (range, 8 to 42) after the experimental solution was begun. CONCLUSIONS: In this pilot trial involving 10 neonates who had surgery for congenital bowel abnormalities, the enteral administration of a sterile, isotonic, amniotic fluid-like solution was tolerated.

Tolerance of a sterile isotonic electrolyte solution containing select recombinant growth factors in neonates recovering from necrotizing enterocolitis.

OBJECTIVE: To assess the tolerance of a sterile isotonic electrolyte solution containing select recombinant growth factors enterally administered in neonates who were NPO because of necrotizing enterocolitis (NEC). STUDY DESIGN: A phase I trial was accomplished among 30 neonates. Patients received 5, 10, or 20 mL enterally of the study solution/kg/day divided into every 3-hour dosing, for 3 days prior to when feedings of milk were to resume. The occurrence of emesis, gastric residuals, diarrhea, bloody stools, abdominal distention, skin rashes and death were sought. RESULTS: Gestational ages ranged from 25.2 to 41.1 weeks. A total of 16 neonates had Stage IA NEC, six Stage IB, and eight Stage IIA. The solution was well tolerated in all 30; none developed diarrhea, guaiac positive or bloody stools, or abdominal distention. Administration of the solution was not prematurely discontinued in any infant. Two neonates died secondary to late-onset sepsis remote from the study period. CONCLUSIONS: Enteral administration of a sterile isotonic electrolyte solution containing select recombinant growth factors was well tolerated by neonates with NEC.

Effect of recombinant erythropoietin on "late" transfusions in the neonatal intensive care unit: a meta-analysis.

OBJECTIVES: Using the approach of a meta-analysis, we sought to determine whether the administration of recombinant erythropoietin (rEpo) to very low birth weight (VLBW) infants, after the first week of life, results in fewer "late" transfusions. STUDY DESIGN AND METHODS: The guidelines set forth by the Cochrane Neonatal Review Group were used to identify all relevant studies. Medline was searched from January 1990 to November of 2000. Studies that used a randomized, placebo-controlled, and double-masked design were deemed acceptable. RESULTS: Eight studies meet the inclusion criteria. These involved 357 VLBW neonates: 183 rEpo and 174 placebo recipients. The neonates in the rEpo group received fewer erythrocyte transfusions during the study period than did those in the placebo group; the common odds ratio (OR)=0.33; 95% confidence interval (CI) 0.21-0.51. Furthermore, the rEpo effect size was a function of the dose of rEpo administered (p=0.0001). CONCLUSION: A meta-analysis of the most scientifically rigorous studies on this topic indicates that administration of rEpo to VLBW infants reduces "late" erythrocyte transfusions in a dose-dependent manner.