International guidelines regarding the role of IVIG in the management of Rh- and ABO-mediated haemolytic disease of the newborn
Lieberman L, Lopriore E, Baker JM, Bercovitz RS, Christensen RD, Crighton G, Delaney M, Goel R, Hendrickson JE, Keir A, et al
British journal of haematology. 2022
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Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN.
Effect of blood transfusions on cognitive development in very low birth weight infants
Shah P, Cannon DC, Lowe JR, Phillips J, Christensen RD, Kamath-Rayne B, Rosenberg A, Wiedmeier S, Patel S, Winter S, et al
Journal of perinatology : official journal of the California Perinatal Association. 2021
OBJECTIVE Preterm infants frequently receive red cell transfusions; however, the effect of transfusions on cognition is unclear. We evaluated the relationship between transfusions and cognitive outcomes in preterm infants enrolled in a randomized trial of erythropoiesis stimulating agents (ESAs). STUDY DESIGN Preterm infants were randomized to ESAs or placebo during initial hospitalization, and transfusions recorded. Children were evaluated using standard developmental tests of cognition at 18-22 months (56 ESA, 24 placebo) and 3.5-4 years (39 ESA, 14 placebo). RESULTS Cognitive scores at 18-22 months were inversely correlated with transfusion volume (p = 0.02). Among those receiving ≥1 transfusion, cognitive scores were significantly higher in the ESA-treated group (p = 0.003). At 3.5-4 years, transfusions were not correlated with cognitive scores. CONCLUSIONS In the placebo group, transfused children had lower cognitive scores than did non-transfused children at 18-22 months. In the ESA group, cognitive scores did not differ by transfusion status, suggesting ESAs might provide neuroprotection.
Transfusing neonates based on platelet count vs. platelet mass: A randomized feasibility-pilot study
Zisk JL, Mackley A, Clearly G, Chang E, Christensen RD, Paul DA
Abstract The objective of this study was to obtain pilot data on which to judge the feasibility and sample size needed for a future comparative-effectiveness trial of platelet transfusions in the NICU. We conducted a limited-scope pilot trial in which neonates were randomized to receive platelet transfusions based on platelet mass vs. platelet count, using preset "transfusion-trigger" values. Analysis included parental consent rate, number of platelet transfusions given, bleeding episodes recorded, and mortality rate. Statistical analysis included ANOVA and Chi-square. A convenience sample of 30 were randomized; 15 per group. No differences were found between groups in gestational age, birth weight, race, gender or clinical diagnoses. The study consent rate was 52% (30/58). No differences were found in number of platelet transfusions received, bleeding episodes, or mortality. Lack of a trend in transfusion-reduction resulted in inability to estimate the number needed in a future comparative-effectiveness trial. Using platelet mass, rather than platelet count, for a NICU platelet transfusion trigger is feasible. However, any future comparative-effectiveness trial, testing the hypothesis that a platelet mass-based trigger reduces the transfusion rate will likely require a very large sample size.
A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants
Ohls RK, Christensen RD, Kamath-Rayne BD, Rosenberg A, Wiedmeier SE, Roohi M, Lacy CB, Lambert DK, Burnett JJ, Pruckler B, et al
BACKGROUND A novel erythropoiesis stimulating agent (ESA), darbepoetin alfa (Darbe), increases hematocrit in anemic adults when administered every 1 to 3 weeks. Weekly Darbe dosing has not been evaluated in preterm infants. We hypothesized that infants would respond to Darbe by decreasing transfusion needs compared with placebo, with less-frequent dosing than erythropoietin (Epo). METHODS Preterm infants 500 to 1250 g birth weight and <=48 hours of age were randomized to Darbe (10 ug/kg, 1 time per week subcutaneously), Epo (400 U/kg, 3 times per week subcutaneously) or placebo (sham dosing) through 35 weeks' gestation. All received supplemental iron, folate, and vitamin E, and were transfused according to protocol. Transfusions (primary outcome), complete blood counts, absolute reticulocyte counts (ARCs), phlebotomy losses, and adverse events were recorded. RESULTS A total of 102 infants (946 +/- 196 g, 27.7 +/- 1.8 weeks' gestation, 51 +/- 25 hours of age at first dose) were enrolled. Infants in the Darbe and Epo groups received significantly fewer transfusions (P = .015) and were exposed to fewer donors (P = .044) than the placebo group (Darbe: 1.2 +/- 2.4 transfusions and 0.7 +/- 1.2 donors per infant; Epo: 1.2 +/- 1.6 transfusions and 0.8 +/- 1.0 donors per infant; placebo: 2.4 +/- 2.9 transfusions and 1.2 +/- 1.3 donors per infant). Hematocrit and ARC were higher in the Darbe and Epo groups compared with placebo (P = .001, Darbe and Epo versus placebo for both hematocrit and ARCs). Morbidities were similar among groups, including the incidence of retinopathy of prematurity. CONCLUSIONS Infants receiving Darbe or Epo received fewer transfusions and fewer donor exposures, and fewer injections were given to Darbe recipients. Darbepoetin and Epo successfully serve as adjuncts to transfusions in maintaining red cell mass in preterm infants.
Very low birth weight infants qualifying for a 'late' erythrocyte transfusion: does giving darbepoetin along with the transfusion counteract the transfusion's erythropoietic suppression?
Warwood TL, Lambert DK, Henry E, Christensen RD
Journal of Perinatology. 2011;31((Suppl 1):):S17-21.
OBJECTIVE Red blood cell (RBC) transfusions can suppress erythropoiesis. On this basis, RBC transfusions administered to very low birth weight (VLBW) neonates potentially render them more likely to qualify for a subsequent transfusion.STUDY DESIGN We hypothesized that 'late' (>14 days after birth) RBC transfusions given to VLBW neonates result in a decrease in reticulocyte count persisting for at least 7 to 10 days. We also hypothesized that a single dose of darbepoetin given along with the transfusion would have the opposite effect, increasing the reticulocyte count for at least 7 to 10 days. To test this, we conducted a single-centered randomized trial with 20 VLBW neonates who, according to our transfusion guidelines, qualified for a late transfusion.RESULT VLBW infants about to receive a late RBC transfusion were randomized (1:1) to also receive vs not receive (controls) a single subcutaneous dose of darbepoetin (10 µgkg(-1)). Reticulocyte counts diminished significantly in the controls (a drop of 85±62 x 10(3) µl(-1) (mean±s.d.) at 7 to 10 days), but increased significantly in the darbepoetin recipients (an increase of 177±120 x 10(3) µl(-1) at 7 to 10 days, P<0.0001). At 7 to 10 days after the transfusion, hematocrits of the controls were 8.1±4.9 points above their pre-transfusion values and of the darbepoetin group were 12.4±2.7 points above their pre-transfusion values (P=0.033).CONCLUSION This was a limited-scope, single-centered, randomized trial intended to pilot-test a new concept in neonatal transfusion practice. Namely, we tested whether a late RBC transfusion suppressed reticulocytosis and whether a concomitant single dose of darbepoetin counteracted that suppression. Using the pilot data presented in this study, larger trials can now be designed to address meaningful clinical outcomes such as transfusion avoidance using this approach.
Single-dose darbepoetin administration to anemic preterm neonates
Warwood TL, Ohls RK, Wiedmeier SE, Lambert DK, Jones C, Scoffield SH, Neeraj G, Veng-Pedersen P, Christensen RD
Journal of Perinatology. 2005;25((11):):725-30.
Objective: Darbepoetin is longer acting and more potent than recombinant erythropoietin (rEpo). In certain situations, preterm neonates might benefit from rEpo, and for such patients darbepoetin would require fewer doses at a lower cost. However, the proper dose and dosing interval have not been established. Study design: We performed a prospective trial in two level III Neonatal Intensive Care Units. Patients <32 weeks gestation at birth, with a birth weight (BW) <1500g, were eligible for participation if they were >21-days-old and had a hemoglobin (Hgb) concentration <=10. 5g/dl. In all, 12 were to receive a single subcutaneous (s. c. ) dose at either 1 or 4 mug/kg. Once before the dose was given, and at two preset intervals after, blood was obtained for immature reticulocyte fraction (IRF) and absolute reticulocyte count (ARC). Once before and at four preset intervals after, blood was obtained for pharmacokinetic studies. Results: The 12 subjects had BWs of 1129+/-245g (mean+/-SD), were 29. 2+/-1. 2 weeks gestation at delivery, and were 43+/-12 days old with an Hgb concentration of 9. 6+/-1. 0g/dl when the darbepoetin was given. Six received 1 mu;g/kg and six 4 mug/kg. The IRF increased (p<0. 05) as did the ARC (p<0. 05). The increases in IRF were somewhat greater among the 4 mug/kg recipients (P =0. 06). The highest recorded concentrations of drug occurred 6 to 12 hours after administration. The combined 6 and 12 hours values were 185+/-106mU/ ml in the 1 mug/kg group vs 597+/-238 in the 4 mug/kg group (p<0. 002). The t 1/2 was 26 hours (range 10 to 50). The biovailability-normalized clearance was 19ml/hour/kg (range 5 to 54). Conclusions: A single s. c. dose of darbepoetin given to preterm neonates accelerated effective erythropoiesis. The pharmacodynamic and pharmacokinetic findings suggest that darbepoetin dosing in neonates would require a higher unit dose/kg and a shorter dosing interval than are generally used for anemic adults. Copyright © 2011 Elsevier B. V. , Amsterdam. All Rights Reserved.
Absorption of enteral recombinant human erythropoietin by neonates
Juul SE, Christensen RD
The Annals of Pharmacotherapy. 2003;37((6):):782-6.
BACKGROUND Erythropoietin (EPO) is present in amniotic fluid, colostrum, and human milk. One possible function of ingested EPO might be to stimulate erythropoiesis. However, it is unclear whether human neonates absorb recombinant human erythropoietin (rhEPO) after oral administration. OBJECTIVE To determine whether circulating EPO concentrations increase following enteral administration of rhEPO to neonates. METHODS The study was designed as a 2-center prospective, blinded, randomized, 2 x 2 crossover study, with each infant receiving 1 dose of rhEPO 1000 units/kg and 1 dose of placebo. Serum EPO concentrations were measured at baseline, 2, and 4 hours following study drug administration. The rhEPO and placebo dosing were separated by a mean of 72 hours. Analysis was stratified by gestational age (< or =35 wk, >35 wk) and feeding type (human milk, infant formula). RESULTS No significant change in serum EPO concentration was identified at 2 or 4 hours following enteral administration of rhEPO. CONCLUSIONS Enteral administration of a large dose of rhEPO to neonates <4 months of age did not result in increased circulating EPO concentrations at 2 or 4 hours following dosing, regardless of whether it was administered in human milk or infant formula.
The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double-blind, placebo-controlled study
Ohls RK, Harcum J, Schibler KR, Christensen RD
Journal of Pediatrics. 1997;131((5):):661-5.
BACKGROUND Clinical trials of erythropoietin (EPO) administration to preterm infants have not focused on infants weighing 750 gm or less, the population most likely to receive multiple transfusions because of large phlebotomy losses. It is unknown whether preterm infants weighing 750 gm or less will respond to EPO by accelerating erythropoiesis, or whether EPO administered to this population will decrease blood transfusions. METHODS We randomly assigned 28 extremely low birth weight preterm infants (mean +/- SEM: 24.7 +/- 0.3 weeks' gestation, 662 +/- 14 gm birth weight), in the first 72 hours of life, to receive either EPO (200 U/kg/day) or placebo for 14 days and administered transfusions only according to protocol over a 21-day study period. All infants received 1 mg/kg/day iron dextran in their total parenteral nutrition solution during the 14-day treatment period. RESULTS During the 21-day study period, a lower number and volume of transfusions were received by the EPO recipients (4.7 +/- 0.7 transfusions per patient and 70 +/- 11 ml/kg per patient) than by the placebo recipients (7.5 +/- 1.1 transfusions per patient and 112 +/- 17 ml/kg per patient; p < 0.05, EPO vs placebo), whereas hematocrits remained similar in the two groups. Reticulocyte counts were similar in both groups on day 1 but were greater in the EPO recipients on day 14 (EPO day 1, 351 +/- 53; EPO day 14, 359 +/- 40 x 10(3)/microl; placebo day 1, 334 +/- 64; placebo day 14, 120 +/- 10 x 10(3)/microl; p < 0.01, EPO vs placebo). Serum ferritin concentrations were similar in both groups at the beginning of the study but were greater in the placebo recipients by day 14 (EPO, 262 +/- 44 microg/L; placebo, 593 +/- 92 microg/L; p < 0.01). No adverse effects of EPO or iron were noted. CONCLUSION The combination of EPO and parenteral iron stimulates erythropoiesis in preterm infants weighing 750 gm or less and results in fewer transfusions during their first 3 weeks of life.
Pharmacokinetics and effectiveness of recombinant erythropoietin administered to preterm infants by continuous infusion in total parenteral nutrition solution
Ohls RK, Veerman MW, Christensen RD
Journal of Pediatrics. 1996;128((4):):518-23.
OBJECTIVES To compare the pharmacokinetics and effectiveness of continuously administered recombinant erythropoietin (Epo) in total parenteral nutrition (TPN) solution with daily subcutaneously administered Epo. METHODS Forty preterm infants in the first 72 hours of life were randomly assigned to receive Epo (200 units/kg per day for 10 consecutive days), either subcutaneously (20 infants, 1051 +/- 40 gm, 28.3 +/- 0.4 weeks of gestation; mean +/- SEM), or added daily to their TPN fluids (20 infants, 1028 +/- 36 gm, 27.9 +/- 0.4 weeks of gestation). Both groups received iron supplementation (1 mg/kg per day iron dextran in the TPN solution). Absolute reticulocyte counts and complete blood cell counts with differentials were measured, and transfusions and phlebotomy losses were recorded. Pharmacokinetics were determined in the first 16 infants. RESULTS In the infants who received Epo subcutaneously, the elimination half-life was 17.6 +/- 4.4 hours on day 3 and 11.2 +/- 1.5 hours on day 10; the volume of distribution was 802 +/- 190 ml/kg on day 3 and 1330 +/- 243 m/kg on day 10. Serum Epo concentrations were higher on day 3 than on day 10 for both groups (subcutaneous: 400 +/- 64 mU/ml vs 177 +/- 29 mU/m, p <0.05; TPN: 395 +/- 64 vs 194 +/- 41 mU/ml, p <0.05). Clearance did not differ between the two groups with regard to route of administration and increased significantly from days 3 to 10 in both groups. Reticulocyte counts were similar in both groups. There were no differences between groups in the number of transfusions given, and the overall decline in hematocrit was similar. No adverse effects of Epo were noted in either group. CONCLUSIONS Adding Epo to the TPN solution in this population results in similar Epo concentrations, clearance, and effectiveness as subcutaneous dosing.
Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: a randomized, placebo-controlled trial
Ohls RK, Osborne KA, Christensen RD
Journal of Pediatrics. 1995;126((3):):421-6.
OBJECTIVE We hypothesized that using a higher dose of erythropoietin (Epo) and starting treatment on the first day of life would reduce the transfusion requirements of ventilator-dependent and non-ventilator-dependent very low birth weight (VLBW) infants. Moreover, we hypothesized that this treatment would be cost-effective. METHODS We randomly assigned 20 ill newborn VLBW infants to receive either Epo (200 units/kg per day) or placebo during their first 2 weeks of life. The caregivers were unaware of the treatment assignments, and erythrocyte transfusions were administered according to hematocrit and signs of anemia. RESULTS On day 1, reticulocyte counts and hematocrits were similar in the two groups. During the subsequent 2 weeks, reticulocyte counts of the placebo recipients fell significantly below those of the Epo recipients, but hematocrits in the two groups did not differ. More transfusions were received by the placebo recipients (mean = 1.4 per patient) than by the Epo recipients (mean = 0.2 per patient; p < 0.01). No adverse effects of Epo were noted, and the costs in the placebo group exceeded those in the Epo group. CONCLUSIONS We conclude that administration of Epo to VLBW infants during the first 2 weeks of life results in fewer transfusions and is cost-effective.