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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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Abstract
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.
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Immunoglobulin for alloimmune hemolytic disease in neonates
Zwiers C, Scheffer-Rath M E, Lopriore E, de Haas M, Liley H G
The Cochrane Database of Systematic Reviews. 2018;3
Abstract
BACKGROUND Exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological complications. Because of the risks and burdens of exchange transfusion, intravenous immunoglobulin (IVIg) has been suggested as an alternative therapy for alloimmune hemolytic disease of the newborn (HDN) to reduce the need for exchange transfusion. OBJECTIVES To assess the effect and complications of IVIg in newborn infants with alloimmune HDN on the need for and number of exchange transfusions. SEARCH METHODS We performed electronic searches of CENTRAL, PubMed, Embase (Ovid), Web of Science, CINAHL (EBSCOhost), Academic Search Premier, and the trial registers ClinicalTrials.gov and controlled-trials.com in May 2017. We also searched reference lists of included and excluded trials and relevant reviews for further relevant studies. SELECTION CRITERIA We considered all randomized and quasi-randomized controlled trials of IVIg in the treatment of alloimmune HDN. Trials must have used predefined criteria for the use of IVIg and exchange transfusion therapy to be included. DATA COLLECTION AND ANALYSIS We used the standard methods of Cochrane and its Neonatal Review Group. We assessed studies for inclusion and two review authors independently assessed quality and extracted data. We discussed any differences of opinion to reach consensus. We contacted investigators for additional or missing information. We calculated risk ratio (RR), risk difference (RD) and number needed to treat for an additional beneficial outcome (NNTB) for categorical outcomes. We calculated mean difference (MD) for continuous variables. We used GRADE criteria to assess the risk of bias for major outcomes and to summarize the level of evidence. MAIN RESULTS Nine studies with 658 infants fulfilled the inclusion criteria. Term and preterm infants with Rh or ABO (or both) incompatibility were included. The use of exchange transfusion decreased significantly in the immunoglobulin treated group (typical RR 0.35, 95% CI 0.25 to 0.49; typical RD -0.22, 95% CI -0.27 to -0.16; NNTB 5). The mean number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (MD -0.34, 95% CI -0.50 to -0.17). However, sensitivity analysis by risk of bias showed that in the only two studies in which the treatment was masked by use of a placebo and outcome assessment was blinded, the results differed; there was no difference in the need for exchange transfusions (RR 0.98, 95% CI 0.48 to 1.98) or number of exchange transfusions (MD -0.04, 95% CI -0.18 to 0.10). Two studies assessed long-term outcomes and found no cases of kernicterus, deafness or cerebral palsy. AUTHORS' CONCLUSIONS Although overall results show a significant reduction in the need for exchange transfusion in infants treated with IVIg, the applicability of the results is limited because of low to very low quality of evidence. Furthermore, the two studies at lowest risk of bias show no benefit of IVIg in reducing the need for and number of exchange transfusions. Based on these results, we have insufficient confidence in the effect estimate for benefit of IVIg to make even a weak recommendation for the use of IVIg for the treatment of alloimmune HDN. Further studies are needed before the use of IVIg for the treatment of alloimmune HDN can be recommended, and should include blinding of the intervention by use of a placebo as well as sufficient sample size to assess the potential for serious adverse effects.
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Immunoglobulins in neonates with rhesus hemolytic disease of the fetus and newborn: long-term outcome in a randomized trial
van Klink JM, van Veen SJ, Smits-Wintjens VE, Lindenburg IT, Rijken M, Oepkes D, Lopriore E
Fetal Diagnosis and Therapy. 2016;39((3)):209-13.
Abstract
OBJECTIVE Prophylactic intravenous immunoglobulin (IVIg) does neither reduce the need for exchange transfusion nor the rates of other adverse neonatal outcomes in neonates with rhesus hemolytic disease of the fetus and newborn (rhesus HDFN) according to our randomized controlled trial analysis. Our objective was to assess the long-term neurodevelopmental outcome in the children included in the trial and treated with either IVIg or placebo. METHODS All families of the children included in the trial were asked to participate in this follow-up study. The long-term neurodevelopmental outcome in children at least 2 years of age was assessed using standardized tests. The primary outcome was the incidence of neurodevelopmental impairment defined as at least one of the following: cerebral palsy, severe cognitive and/or motor developmental delay (with a test score of less than -2 SD), bilateral deafness or blindness. RESULTS Sixty-six of the 80 children (82.5%) who had been recruited to the initial randomized controlled trial participated in the follow-up study. The children were assessed at a median age of 4 years (range 2-7). The median cognitive score was 96 (range 68-118) in the IVIg group and 97 (range 66-118) in the placebo group (p = 0.79). There was no difference in the rate of neurodevelopmental impairment between the IVIg and the placebo group [3% (1/34) vs. 3% (1/32); p = 1.00]. CONCLUSIONS The long-term neurodevelopmental outcome in children treated with IVIg was not different from that in children treated with placebo. Standardized long-term follow-up studies with large enough case series and sufficient power are needed to replicate these findings. (c) 2015 S. Karger AG, Basel.
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Low-dose versus standard-dose intravenous immunoglobulin to prevent fetal intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia: a randomized trial
Paridaans NP, Kamphuis MM, Taune Wikman A, Tiblad E, Van denAkker ES, Lopriore E, Challis D, Westgren M, Oepkes D
Fetal Diagnosis & Therapy. 2015;38((2)):147-53.
Abstract
OBJECTIVE Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e. 0.5 g/kg. METHODS This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH. RESULTS A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 x 10(9)/l (range 8-269) in the 0.5 g/kg group versus 110 x 10(9)/l (range 11-279) in the 1 g/kg group (p = 0.644). CONCLUSION The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose. © 2015 S. Karger AG, Basel.
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Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial
Smits-Wintjens VE, Walther FJ, Rath ME, Lindenburg IT, Pas AB, Kramer CM, Oepkes D, Brand A, Lopriore E
Pediatrics. 2011;127((4):):680-6.
Abstract
BACKGROUND Despite limited data, international guidelines recommend the use of intravenous immunoglobulin (IVIg) in neonates with rhesus hemolytic disease.OBJECTIVE We tested whether prophylactic use of IVIg reduces the need for exchange transfusions in neonates with rhesus hemolytic disease.DESIGN AND SETTING We performed a randomized, double-blind, placebo-controlled trial in neonates with rhesus hemolytic disease. After stratification for treatment with intrauterine transfusion, neonates were randomly assigned for IVIg (0.75 g/kg) or placebo (5% glucose). The primary outcome was the rate of exchange transfusions. Secondary outcomes were duration of phototherapy, maximum bilirubin levels, and the need of top-up red-cell transfusions.RESULTS Eighty infants were included in the study, 53 of whom (66%) were treated with intrauterine transfusion(s). There was no difference in the rate of exchange transfusions between the IVIg and placebo groups (7 of 41 [17%] vs 6 of 39 [15%]; P = .99) and in the number of exchange transfusions per patient (median [range]: 0 [0-2] vs 0 [0-2]; P = .90) or in duration of phototherapy (4.7 [1.8] vs 5.1 [2.1] days; P = .34), maximum bilirubin levels (14.8 [4.7] vs 14.1 [4.9] mg/dL; P = .52), and proportion of neonates who required top-up red-cell transfusions (34 of 41 [83%] vs 34 of 39 [87%]; P = .76).CONCLUSIONS Prophylactic IVIg does not reduce the need for exchange transfusion or the rates of other adverse neonatal outcomes. Our findings do not support the use of IVIg in neonates with rhesus hemolytic disease.
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The use of IVIg in the management of haemolytic disease of the newborn: Leiden's IVIg trial in rhesus disease of the neonate (Livin-Study)
Smits-Wintjens VEHJ, Lopriore E, Walther FJ, Oepkes D, Kanhai HH, Brand A
Transfusion Medicine. 2009;19((Suppl 1):):7. Abstract No. S106.