Reconciling markedly discordant values of serum ferritin versus reticulocyte hemoglobin content.

OBJECTIVE: To determine why serum ferritin and reticulocyte hemoglobin (RET-He), drawn to assess neonatal iron sufficiency, sometimes have markedly discordant results. STUDY DESIGN: Retrospective records review of five NICUs over 28 months, identifying all patients with a ferritin and RET-He within 48 h. We examined records of all who had marked discordance (one value >95th % reference interval, the other <5th %). RESULTS: Of 190 paired ferritin and RET-He measurements, 16 (8%) were markedly discordant. Fifteen of the 16 discordant samples involved a high ferritin and a low RET-He. In these, low MCV and high %Micro-R, and low MCH and high %HYPO-He were present. In total, 8 of the 15 had laboratory or clinical evidence of an inflammatory process and five had suspicion of infection documented. CONCLUSIONS: When ferritin and RET-He were discordant, erythrocyte microcytosis and hypochromasia suggested that the RET-He gave the more accurate interpretation; that iron deficiency was likely present.

Exchange transfusion for hemolytic hyperbilirubinemia: could some be averted by emergent administration of an inhibitor of bilirubin production?

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.

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.

Neonates with suspected microangiopathic disorders: performance of standard manual schistocyte enumeration vs. the automated fragmented red cell count.

OBJECTIVES: To enhance the diagnosis of schistocyte-producing conditions, we compared routine manual schistocyte enumeration with automated fragmented red cell counts (FRCs). STUDY DESIGN: In neonates "suspected" of having sepsis, NEC, or DIC we compared manual schistocyte estimates vs. automated FRC counts. When the two disagreed, we used a "gold standard" from a  ≥ 1000 RBC differential. We also assessed the diagnostic accuracy of the FRC count in diagnosing sepsis, NEC, or DIC. RESULTS: We collected 270 CBCs from 90 neonates. The methods agreed in 63% (95% CI 55%-70%) of the CBCs. Among the 37% where they disagreed, the FRC count was more accurate in 100% (95% CI 88-100%). An elevated FRC count was specific for sepsis, and was sensitive and specific for necrotizing enterocolitis and DIC. CONCLUSIONS: Automated FRC counts have advantages over routine manual evaluation, larger sample size, lower expense, and superior accuracy in diagnosing schistocyte-producing conditions.

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.

Evaluating Otherwise-Discarded Umbilical Cord Blood as a Source for a Neonate's Complete Blood Cell Count at Various Time Points.

BACKGROUND: Previous studies have reported the use of cord blood for admission laboratory complete blood counts (CBCs). However, no studies have investigated its stability for the first 30 min after delivery. OBJECTIVES: We quantified blood cells drawn from the umbilical vein to determine the effect of (1) the time after placental delivery, and (2) the site of blood sampling (umbilical vein on an isolated cord segment vs. umbilical vein on the placental surface). METHODS: Timed phlebotomies were drawn at 2, 10, and 30 min from (1) the umbilical vein on an isolated, double-clamped cord segment, and (2) the umbilical vein near or on the placental surface. Leukocyte count, hemoglobin, platelet count, and fibrinogen were measured on each phlebotomy sample. RESULTS: Blood drawn from the isolated umbilical cord segments had leukocyte count, hemoglobin, platelet count, and fibrinogen that remained unchanged between the phlebotomies at 2, 10, and 30 min after delivery. However, blood drawn from the umbilical vein on the placental surface had, at 30 min, a leukocyte count (p = 0.002), hemoglobin (p = 0.01), and platelet count (p = 0.001) that were statistically different from the values at 2 and 10 min after delivery. There was no difference in fibrinogen at 2, 10, or 30 min. CONCLUSIONS: If cord blood is used for a neonate's initial CBC, the blood should be drawn within 10 min of the placental delivery when it is taken from the umbilical vein on or near the placenta. If an umbilical cord segment is obtained, the phlebotomy can be delayed for up to 30 min.

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.

Bilirubin levels and phototherapy use before and after neonatal red blood cell transfusions.

BACKGROUND: Our previous retrospective study suggested that red blood cell (RBC) transfusion of preterm neonates can be associated with an increase in bilirubin, but this has not been tested prospectively. STUDY DESIGN AND METHODS: We studied neonates before and after RBC transfusions, recording serial bilirubin levels and whether they qualified for phototherapy. Because lysed RBCs release plasma-free hemoglobin (Hb), a precursor to bilirubin, we also measured plasma free Hb and bilirubin from the donor blood. RESULTS: We studied 50 transfusions given to 39 neonates. Gestation ages of transfused neonates, at birth, were 26 (24-29) weeks (median [interquartile range]); birthweights were 750 (620-1070) g. The study transfusion was given on Day of Life 9.9 (3.4-19.2). In 20% (10/50) phototherapy was being administered at the beginning of and during the transfusion. In these patients neither the 4- to 6- nor the 24- to 36-hour-posttransfusion bilirubin levels were significantly higher than before transfusion. However, in 30% of the others (12/40) phototherapy was started (or restarted) after the transfusion and 15% had a posttransfusion bilirubin increase of at least 2.5 mg/dL. These neonates received donor blood with a higher plasma-free Hb (p < 0.05). CONCLUSIONS: Neonates commonly qualify for phototherapy after transfusion. A minority (15% in this series) have a posttransfusion bilirubin increase of at least 2.5 mg/dL. We speculate that neonates qualifying for a RBC transfusion, who are judged to be at high risk for bilirubin-induced neurotoxicity, might benefit from checking their serum bilirubin level after the transfusion and providing donor blood with low plasma-free Hb levels.

Measuring End-Tidal Carbon Monoxide of Jaundiced Neonates in the Birth Hospital to Identify Those with Hemolysis.

BACKGROUND: End-tidal breath carbon monoxide (ETCOc) levels correlate with catabolism of heme, but until recently, this measurement was not readily available for application to neonatology practice. OBJECTIVES: We performed a prospective, multihospital, test-of-concept study where ETCOc was measured during the birth hospitalization of neonates with a total bilirubin (TB) value >75th percentile on the Bhutani bilirubin nomogram. This was done to test the feasibility and ease of use of this new device. METHODS: Neonates with an elevated ETCOc (with a >95th percentile reference interval previously established) were labeled as having 'hemolytic jaundice'. We recommended a follow-up TB check <24 h after hospital discharge to these families. RESULTS: One hundred and fifteen neonates were eligible for the study, the parents of 103 provided consent, and measurements were obtained for 100. Sixty-three had normal and 37 had elevated ETCOc values. By means of a direct antiglobulin test (DAT; Coombs), 11 of these 37 were found positive for ABO hemolytic disease; the remaining 26 had other etiologies. Thirty-six of the 37 with an elevated ETCOc had repeat TB monitoring <24 h after discharge home. None of the 100 were rehospitalized for jaundice treatment compared with a rate of 2.99 rehospitalizations per 100 control neonates who had a TB value >75th percentile (p = 0.079). CONCLUSION: ETCOc measurement is a feasible means of assessing hemolysis in jaundiced neonates during the birth hospitalization. When hemolysis is identified, parents are likely to comply with instructions to bring the infant for a TB checkup <24 h after discharge home.

Early-Onset Neutropenia in Small-for-Gestational-Age Infants.

BACKGROUND: Early neutropenia is more common in small for gestational age (SGA) neonates (birth weight <10th percentile) than in appropriately grown neonates. However, several aspects of this variety of neutropenia are unknown, including the duration, kinetic mechanism, and outcomes. METHODS: Using 10 years of multihospital records, we studied SGA neonates who, during the first week after birth, had neutrophil counts <1000/µL. RESULTS: This degree of neutropenia was more common in SGA neonates (6%, 207/3650) than in non-SGA matched controls (1%, 46/3650; P < .001). Neutrophil counts stayed below the lower reference interval for 7 days. Ratios of immature to total neutrophils were within the reference interval, suggesting reduced neutrophil production, not accelerated neutrophil use or destruction. Increased nucleated red cells at birth correlated with decreased neutrophils (P < .001). Neutropenia was not independently associated with maternal hypertensive disorders, over and above the effect of SGA. Of 201 neutropenic SGA neonates, 129 (64%) also had thrombocytopenia. Sixteen percent of neutropenic neonates were treated with recombinant granulocyte colony-stimulating factor (rG-CSF) or intravenous immunoglobulin (IVIG), with no reduction in late-onset sepsis or necrotizing enterocolitis (NEC). Regression analysis showed that neutropenia (but not thrombocytopenia in the absence of neutropenia) was independently associated with increased odds of developing necrotizing enterocolitis (odds ratio 4.01, 90% confidence interval 2.08 to 7.35, P < .001). CONCLUSIONS: Neutropenia of SGA is a condition of 1-week duration. It is more closely associated with SGA than maternal hypertension (likely owing to neutrophil hypoproduction associated with intrauterine hypoxia), often accompanied by thrombocytopenia, not obviously improved by rG-CSF or IVIG, and associated with an increased risk for NEC.

Thrombocytopenia in Small-for-Gestational-Age Infants.

BACKGROUND: Thrombocytopenia is common among small-for-gestational-age (SGA) neonates (birth weight <10th percentile reference range), but several aspects of this thrombocytopenia are unclear, including the incidence, typical nadir, duration, association with preeclampsia, mechanism, and risk of death. METHODS: Using 9 years of multihospital records, we studied SGA neonates with ≥2 platelet counts <150,000/µL in their first week. RESULTS: We found first-week thrombocytopenia in 31% (905 of 2891) of SGA neonates versus 10% of non-SGA matched controls (P < .0001). Of the 905, 102 had a recognized cause of thrombocytopenia (disseminated intravascular coagulation, early-onset sepsis, or extracorporeal membrane oxygenation). This group had a 65% mortality rate. The remaining 803 did not have an obvious cause for their thrombocytopenia, and we called this "thrombocytopenia of SGA." They had a mortality rate of 2% (P < .0001) and a mean nadir count on day 4 of 93,000/µL (SD 51,580/µL, 10th percentile 50,000/µL, 90th percentile 175,000/µL). By day 14, platelet counts were ≥150,000/µL in more than half of the patients. Severely SGA neonates (<1st percentile) had lower counts and longer thrombocytopenia duration (P < .001). High nucleated red cell counts at birth correlated with low platelets (P < .0001). Platelet transfusions were given to 23%, and counts typically more than tripled. Thrombocytopenia was more associated with SGA status than with the diagnosis of maternal preeclampsia. CONCLUSIONS: SGA neonates with clearly recognized varieties of thrombocytopenia have a high mortality rate. In contrast, thrombocytopenia of SGA is a hyporegenerative condition of moderate severity and 2 weeks' duration and is associated with evidence of intrauterine hypoxia and a low mortality rate.

Thrombocytopenia in late preterm and term neonates after perinatal asphyxia.

BACKGROUND: A recent NHLBI conference concluded that platelet (PLT) transfusions of neonates must become more evidence based. One neonatal disorder for which transfusions are given is a poorly defined entity, the "thrombocytopenia of perinatal asphyxia." To expand the evidence base for this entity, we performed a multicentered, retrospective analysis of neonates with perinatal asphyxia. STUDY DESIGN AND METHODS: We analyzed records of term and late preterm neonates with perinatal asphyxia defined by a cord blood pH of not more than 6.99 and/or base deficit of at least 16 mmol/L. From these we identified neonates with at least two PLT counts of fewer than 150 × 10(9) /L in the first week of life and described the severity, nadir, and duration of the thrombocytopenia. RESULTS: Thrombocytopenia occurred in 31% (117/375) of neonates with asphyxia versus 5% of matched nonasphyxiated controls admitted to a neonatal intensive care unit (p < 0.0001). Twenty-one of the 117 asphyxiated neonates were excluded from the remaining analysis due to disseminated intravascular coagulation or extracorporeal membrane oxygenation. Nadir PLT counts of the remaining 96 were on Day 3 (75 × 10(9) /L; 90% confidence interval, 35.7 × 10(9) -128.6 × 10(9) /L) and normalized by Days 19 to 21. PLT counts after asphyxia roughly correlated inversely with elevated nucleated red blood cell count (NRBC) counts at birth. Thirty of the 96 received at least one PLT transfusion, all given prophylactically, none for bleeding. CONCLUSIONS: We maintain that the thrombocytopenia of perinatal asphyxia is an authentic entity. Its association with elevated NRBC counts suggests that hypoxia is involved in the pathogenesis. Because PLT counts are only moderately low, the condition is transient, and bleeding problems seem rare, we speculate that PLT transfusions should not be needed for most neonates with this condition.

Association of neonatal red blood cell transfusion with increase in serum bilirubin.

BACKGROUND: It is not clear whether red blood cell (RBC) transfusions typically increase a neonate's total serum bilirubin (TSB) level or if so by how much. STUDY DESIGN AND METHODS: In this retrospective analysis, from 2009 through 2012, we collected TSB measurements before and after transfusions, recording blood types of mothers, neonates, and blood donors and whether phototherapy was used before, during, or after transfusion. RESULTS: Of 7272 neonates admitted during this period, 658 (9%) received 2597 RBC transfusions. TSB levels were drawn before and after 431 transfusions, 255 of which did not have phototherapy at the time the transfusion was administered. The mean increase in TSB was 2.2 mg/dL (95% confidence interval, 1.9-2.5 mg/dL). Seven percent of all transfusions and 12% of transfusions to very-low-birthweight (VLBW) infants (<1500 g) were followed by a TSB increase of at least 5 mg/dL. Transfusions with "universal donor" blood (O-) resulted in a higher TSB increase (p < 0.0001), but the magnitude was clinically insignificant (0.3 mg/dL). Older blood (days since donor draw) did not generate significantly higher posttransfusion TSB levels (p = 0.092). A focused study of the 10 neonates with the highest TSB increases revealed that six were unexplained other than transfusion related. CONCLUSIONS: We describe an association between RBC transfusion and TSB elevation, but we recognize that this does not establish a cause-and-effect relationship. However, the observation that an increase of at least 5 mg/dL occurs after 12% of transfusions to VLBW neonates suggests to us that clinicians will want to evaluate jaundice, or measure bilirubin, on VLBW neonates after transfusion.

Reference intervals for common coagulation tests of preterm infants (CME).

BACKGROUND: Fresh-frozen plasma (FFP) is sometimes administered to nonbleeding preterm neonates who are judged to be at risk for bleeding because they have abnormal coagulation tests. The benefits/risks of this practice are not well defined. One limitation to progress is lack of reference intervals for the common coagulation tests, thus limiting precision about whether coagulation tests are indeed abnormal. STUDY DESIGN AND METHODS: In a sequential observational study, fetal blood was drawn at preterm birth (≤ 34 weeks) from the umbilical vein near the placenta. Fibrinogen, prothrombin time, activated partial thromboplastin time, D-dimer, platelet (PLT) count, and mean PLT volume were measured. Reference intervals were constructed using 5th and 95th percentile values. Associations were then sought between abnormal coagulation values at birth and bleeding problems identified during the first week. RESULTS: Coagulation tests were drawn at 175 preterm deliveries and the results were organized into reference intervals by gestational age. No abnormal coagulation value, either alone or in combination, predicted hemorrhage (intraventricular, gastrointestinal, or pulmonary) during the first week. However, fibrinogen exceeding the 95th percentile was associated with evidence of in utero infection/inflammation (correlations with elevated C-reactive protein, p<0.01, and elevated immature to total neutrophil ratio, p<0.001). CONCLUSIONS: Abnormal coagulation values at preterm birth do not predict bleeding during the first week. This suggests to us that bleeding in the days after preterm birth is not generally the result of in utero coagulopathy. These findings bring into question the value of coagulation screening of nonbleeding preterm infants and prophylactic FFP administration to those with abnormal values.

Association, among very-low-birthweight neonates, between red blood cell transfusions in the week after birth and severe intraventricular hemorrhage.

BACKGROUND: Previous reports describe a statistical association, among very-low-birthweight (VLBW, <1500 g) neonates, between red blood cell (RBC) transfusion in the first days after birth and development of severe intraventricular (brain) hemorrhage (IVH). STUDY DESIGN AND METHODS: We hypothesized that after we established a neonatal intensive care unit (NICU) transfusion management program in 2009, a decrease in early (first week after birth) RBC transfusion rate and a decrease in the incidence of severe IVH occurred concomitantly. RESULTS: During a 9-year period 2716 VLBW neonates were admitted to our NICUs. In 2004, 58% of VLBW neonates received one or more RBC transfusions during the first week. After a transfusion compliance program was established in 2009, this rate declined, reaching 25% by 2012. In parallel, the severe IVH rate also declined, from 17% in 2004 to 8% in 2012 (R(2) = 0.73). IVH occurred in 27% of those who received a RBC transfusion during the first week versus less than 2% of those with no early transfusion (p < 0.001). The decrease in IVH rate occurred exclusively among neonates born in an Intermountain Healthcare perinatal center and not among those initially cared for in an "outside" hospital and subsequently transported to an Intermountain NICU. CONCLUSIONS: It remains unclear whether transfusing VLBW neonates during the first days after birth is a proximate cause of IVH. However, the present report is consistent with previous studies showing that successful efforts to reduce early RBC transfusions is associated with a decrease in the incidence of severe IVH.

Unique risks of red blood cell transfusions in very-low-birth-weight neonates: associations between early transfusion and intraventricular hemorrhage and between late transfusion and necrotizing enterocolitis.

Red blood cell transfusions can be life-saving for neonates with severe anemia or active hemorrhage. However, risks of transfusions exist and should always be weighed against potential benefits. At least two transfusion risks are unique to very low birth weight neonates. The first is an association between transfusions given in the first days after birth and the subsequent occurrence of a grade 3 or 4 intraventricular hemorrhage. The second is an association between "late" RBC transfusions and the subsequent occurrence of necrotizing enterocolitis. Much remains to be discovered about the pathogenesis of these two outcomes. Moreover, work is needed to clearly establish whether transfusions are causatively-associated with these outcomes or are co-variables. This review will provide basic data establishing these associations and propose mechanistic explanations.

Necrotizing enterocolitis in term infants.

This article is an overview of NEC in term neonates and also summarizes data from 52 cases within Intermountain Healthcare during the last 11 years. In all 52, NEC occurred among neonates already admitted to a neonatal intensive care unit for some other reason; thus, NEC invariably developed as a complication of treatment, not as a primary diagnosis. The authors speculate that the incidence of term NEC can be reduced by identifying neonatal intensive care unit patients at risk for NEC and applying appropriate-volume human milk feeding programs for these patients.