Immunoglobulin for alloimmune hemolytic disease in neonates.

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.

[Positive Coomb's test in newborns; causes and clinical consequences Summary of cases diagnosed in the Blood Bank in the years 2005 to 2012].

INTRODUCTION: Hemolytic disease of the fetus and newborn (HDFN) is caused by the destruction of fetal red blood cells due to red cell antibodies produced by the mother. HDFN can cause fetal hydrops during pregnancy or neonatal jaundice after birth. Direct Antiglobulin Test (DAT) detects antibodies bound to red cells and is a valuable test aiding in the diagnosis of HDFN. In Iceland DAT is routinely performed on cord blood or newborn blood samples if the mother is Rhesus D negative or has non-A/B red cell alloantibodies. The aim of this study was to investigate the causes and consequences of positive DAT in newborns in Iceland over a period of eight years. MATERIAL AND METHODS: The study population was infants diagnosed with a positive DAT in the Blood Bank in Iceland in the years 2005-2012. Relevant data on the blood group and antibody status of mother and child, blood transfusion and DAT results were retrieved from the Blood Bank information system ProSang. Birth records provided information on birth weight, gestational age and phototherapy. Health records from the Children's Hospital provided information on the management and fate of the newborn. RESULTS: Over the study period 383 newborns had a positive DAT result at the Blood Bank. In 73.6% of cases the underlying cause was ABO blood group mismatch between mother and infant, in 20.4% of cases the mother had non-A/B red cell alloantibodies, in 3.9% both of above factors were present, while in 2.1% the cause was unclear. A total of 179 (47.6%) children had neonatal jaundice that required treatment, of which 167 (93.3%) only needed phototherapy. Eight infants required exchange transfusion, five of these had Rhesus antibodies and three ABO blood group mismatch. CONCLUSION: ABO blood group mismatch between mother and child was the most common cause for a positive DAT in neonates in Iceland in the years 2005-2012. Almost half of the neonates required treatment but usually phototherapy was sufficient. Rarely, blood transfusion or exchange transfusion was necessary in severe cases of ABO blood group mismatch or non-A/B red cell alloantibodies. KEY WORDS: Coombs test, Direct Antiglobulin Test (DAT), Hemolytic disease of the fetus and newborn (HDFN), ABO blood group mismatch, red cell alloantibodies, neonatal jaundice, exchange transfusion. Correspondence: Anna Margret Halldorsdottir, annamha@landspitali.is.

Hemolytic disease of the newborn- anti c antibody induced hemolysis.

Hemolytic disease in the newborn, as a cause of early jaundice, is not uncommon. This is mostly due to Rh (D), ABO incompatibility and rarely due to other minor blood group incompatibility. The authors report two cases of Rh anti c isoimmunization presenting as significant early neonatal jaundice within the 20 h of life. Both the babies were treated with intensive phototherapy. One baby underwent exchange transfusion and the other required packed cell transfusion for anemia.

Hemolytic disease of the newborn associated with anti-Jra alloimmunization in a twin pregnancy: the first case report in Korea.

Jr(a) is a high-frequency antigen found in all ethnic groups. However, the clinical significance of the anti-Jr(a) antibody has remained controversial. Most studies have reported mild hemolytic disease of the newborn and fetus (HDNF) in Jr(a)-positive patients. Recently, fatal cases of HDNF have also been reported. We report the first case of HDNF caused by anti-Jr(a) alloimmunization in twins in Korea. A 33-yr-old nulliparous woman with no history of transfusion or amniocentesis was admitted at the 32nd week of gestation because of vaginal bleeding caused by placenta previa. Anti-Jr(a) antibodies were detected in a routine laboratory examination. An emergency cesarean section was performed at the 34th week of gestation, and 2 premature infant twins were delivered. Laboratory examination showed positive direct antiglobulin test and Jr(a+) phenotype in the red blood cells and the presence of anti-Jr(a) antibodies in the serum in both neonates. The infants underwent phototherapy for neonatal jaundice; this was followed by conservative management. They showed no further complications and were discharged on the 19th postpartum day. Preparative management to ensure the availability of Jr(a-) blood, via autologous donation, and close fetal monitoring must be performed even in cases of first pregnancy in Jr(a-) women.

[High-dose intravenous immunoglobulin therapy and neonatal jaundice due to red blood cell alloimmunization]. / Immunoglobulines polyvalentes intraveineuses et ictère néonatal par allo-immunisation érythrocytaire.

Neonatal jaundice resulting from immunological hemolysis is not uncommon. While it is possible to prevent a large number of Rh-isoimmune hemolytic diseases by administration of specific anti-D immunoglobulins to the mother, the prevention of incompatibility in the ABO groups is not feasible. In spite of advances made in the use of phototherapy, and in order to avoid kernicterus, the treatment of these jaundices can require one or several exchange transfusions (ET), a therapy which is not devoid of risk. For some time now, the data concerning the efficiency of high-dose intravenous immunoglobulin therapy (HDIIT) in the treatment of these jaundices have been increasing. A review of the literature shows that, if used as soon as possible in newborn infants over 32 weeks of gestation age, afflicted with Rh or ABO hemolytic disease, the HDIIT brings about, with no undesirable side effects, a significant decrease in the ET number as well as a significant reduction in the length of phototherapy and hospitalization. The data suggesting that HDIIT could increase the risk of late transfusion is open to controversy.

Enfermedad hemolítica perinatal por dos aloanticuerpos: presentación de un caso / Alloantibody linked perinatal hemolytic disease: case report

La etiopatogenia de la enfermedad hemolítica del recién nacido está basada en la incompatibilidad de grupo sanguíneo entre la madre y el recién nacido. Los neonatos con enfermedad hemolítica por incompatibilidad ABO usualmente tienen madres de grupo O porque la IgG anti-A y anti-B puede atravesar la placenta y sensibilizar los eritrocitos neonatales. Otros anticuerpos además de los ABO han sido reportados como causa de enfermedad hemolítica del recién nacido, ejemplo: anti-D, anti-C, anti-K, anti-Jk, anti-Fy, anti-S, etc. Presentamos el caso de una mujer de 33 años de edad, que en el segundo trimestre de su segunda gestación presentó una hemorragia que motivó la transfusión de una unidad de concentrado de eritrocitos. No se reportó reacción transfusional. El producto de dicha gestación fue un neonato masculino de 2,5 Kg de peso y apgar 6-8 que presentó íctero a las 24 horas después del parto. El fenotipaje ABO de los eritrocitos maternos y del neonato arrojó que la madre era de grupo O y el neonato de grupo B. La prueba de Coombs directa fue positiva 2+ en el neonato y la prueba de Coombs indirecta resultó positiva 3+ en la madre. Dos aloanticuerpos fueron detectados en el suero materno como causa del íctero neonatal, un anti-A y un anti-Jk b. Los eritrocitos maternos fueron fenotipados como Jk b negativos. El tratamiento con fototerapia al neonato se inició a las 40 horas de edad y se prolongó hasta los 10 días de nacido. Una transfusión simple de concentrado de eritrocitos fenotipados fue administrada al neonato a los 8 días de edad.

Islet cell autoantibodies in cord blood from children with blood group incompatibility or hyperbilirubinemia.

Blood group incompatibility is a risk factor for type 1 diabetes. Our aim was to test the hypothesis that islet cell autoantibodies, as markers for beta cell autoimmunity, are increased in cord blood from newborns with a diagnosis of blood group incompatibility. Using the diagnosis register of the Malmö University Hospital we obtained cord blood from 151 children with ABO immunization, 311 children with hyperbilirubinemia and a control group of 320 other children born during the same time period. The cord blood samples were analyzed for islet cell antibodies (ICA) by indirect immunofluorescence and autoantibodies against the Islet Cell Antigen-2 (IA-2Ab) and the 65 kDa isoform of glutamic acid decarboxylase (GAD65Ab) by standard radioligand binding assays. The prevalence of ICA was increased compared to controls (0.6%) not only in children with ABO immunization (4.0%, p = 0.02), but also in newborn children with hyperbilirubinemia (4.2%, p = 0.003). The prevalence of IA2Ab, but not of GAD65Ab, was increased in children with ABO immunization (3.3%) compared to the hyperbilirubinemia group without incompatibility (0.6%, p = 0.04), or the controls (0.3%, p = 0.02). Our findings that hyperbilirubinemia is associated with an increased prevalence of ICA, and blood group incompatibility with both ICA and IA-2, suggests that intra-uterine factors may be associated with islet cell autoimmunity.

Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates.

BACKGROUND: Exchange transfusion and phototherapy have traditionally been used to treat jaundice and avoid the associated neurological complications. Exchange transfusion is not without risk and intravenous immunoglobulin has been suggested as an alternative therapy for isoimmune haemolytic jaundice to reduce the need for exchange transfusion. OBJECTIVES: To assess whether the use of intravenous immunoglobulin, in newborn infants with isoimmune haemolytic jaundice, is effective in reducing the need for exchange transfusion. SEARCH STRATEGY: The search strategy of the Cochrane Neonatal Review group was used. Searches were made of MEDLINE 1966-2002, EMBASE Drugs and Pharmacology 1990-2002, Cochrane Controlled Trials Register, The Cochrane Library, Issue 1, 2002, expert informants, review articles, cross references, and hand searching of abstracts and conference proceedings of the annual meetings of The Society for Pediatric Research 1990-2001 and The European Society for Paediatric Research 1990-2001. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials of the use of intravenous immunoglobulin in the treatment of isoimmune haemolytic disease were considered. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Studies were assessed for inclusion and quality by two reviewers working independently, with the second reviewer blinded to trial author, institution and journal of publication. Data were extracted independently by the two reviewers. Any differences of opinion were discussed and a consensus reached. Investigators were contacted for additional or missing information. For categorical outcomes, the relative risk (RR), risk difference (RD) and the number needed to treat (NNT) were calculated. For continuous variables, the weighted mean difference (WMD) was calculated. MAIN RESULTS: Seven studies were identified. Three of these fulfilled the inclusion criteria and included a total of 189 infants. Term and preterm infants and infants with rhesus and ABO incompatibility were included. The use of exchange transfusion decreased significantly in the immunoglobulin treated group (typical RR 0.28, 95% CI 0.17, 0.47; typical RD -0.37, 95% CI -0.49, -0.26; NNT 2.7). The mean number of exchange transfusions per infant was also significantly lower in the immunoglobulin treated group (WMD -0.52, 95% CI -0.70, -0.35). None of the studies assessed long term outcomes. REVIEWER'S CONCLUSIONS: Although the results show a significant reduction in the need for exchange transfusion in those treated with intravenous immunoglobulin, the applicability of the results is limited. The number of studies and infants included is small and none of the three included studies was of high quality. The protocols of two of the studies mandated the use of early exchange transfusion, limiting the generalizability of the results. Further well designed studies are needed before routine use of intravenous immunoglobulin can be recommended for the treatment of isoimmune haemolytic jaundice.

Isoimmunization is unlikely to be the cause of hemolysis in ABO-incompatible but direct antiglobulin test-negative neonates.

OBJECTIVE: It is stated that the direct antiglobulin (Coombs') test (DAT) may be negative in ABO hemolytic disease of the newborn. Thus, significant jaundice in neonates who are A-B incompatible with their mothers but DAT test negative is often attributed to isoimmunization and another diagnosis is not sought. We wished to determine the rate of bilirubin production, as an objective measure of hemolysis, in 2 groups of DAT-negative neonates--ABO-compatible and ABO-incompatible--and in DAT-positive ABO-incompatible neonates. METHODS: In consecutive, term, healthy newborns who were admitted to the general care nursery, we measured the level in parts per million (ppm) of end-tidal breath carbon monoxide (CO), corrected for inspired CO (ETCOc), an index of the rate of bilirubin production. We compared the levels in DAT-negative ABO-incompatible neonates with those in ABO-compatible neonates and with the levels in DAT-positive ABO-incompatible neonates. Statistical analysis was performed using 2-sample t and chi(2) tests. RESULTS: There was no significant difference between the mean 12-hour ETCOc levels in DAT-negative ABO-incompatible neonates (n = 60, 2.2 +/- 0.6 ppm) versus DAT-negative ABO-compatible neonates (n = 171, 2.1 +/- 0.6 ppm), although there was a difference between the mean levels in DAT-positive ABO-incompatible neonates (n = 14, 3.4 +/- 1.8 ppm) and the DAT-negative groups. Four DAT-negative ABO-incompatible neonates had elevated ETCOc levels; in 2, we diagnosed a specific hematologic abnormality, namely, glucose-6-phosphate dehydrogenase deficiency in 1 and elliptocytosis in the other. CONCLUSION: In DAT-negative newborns with significant jaundice or increased bilirubin production, even if ABO-incompatible, a cause other than isoimmunization should be sought.

In utero development of a warm-reactive autoantibody in a severely jaundiced neonate.

BACKGROUND: The fetus and neonate are widely considered to be immunologically immature. However, there are rare case reports of RBC alloantibody and autoantibody development. STUDY DESIGN AND METHODS: This report describes the case of a severely jaundiced full-term boy neonate presenting at birth with an IgG warm-reactive autoantibody. RESULTS: Mother and neonate were both blood group A, D+. The mother had a negative antibody screen at 18 weeks' gestation and a negative DAT and antibody screen at the time of delivery. The neonate was born with a strongly reactive DAT (IgG) and a panreactive eluate. The serum also contained a panreactive antibody, and all crossmatches were incompatible. The neonate had a bilirubin of 12.5 mg per dL at birth, which peaked at 22.5 mg per dL. However, there was no overt evidence of hemolysis, as evidenced by normal serial Hct levels and reticulocyte counts. The neonate responded well to phototherapy and did not require either simple or exchange transfusion. The neonate's warm-reactive autoantibody maintained its original strength of reactivity on follow-up testing performed at 2 weeks and 2 months of age. CONCLUSIONS: This report describes a rare case of apparent in utero RBC autoantibody development. The fetal/neonatal immune response to blood group antigens is reviewed.

Severe neonatal alloimmune thrombocytopenia due to anti-HPA-3a.

BACKGROUND AND OBJECTIVES: Neonatal alloimmune thrombocytopenia is usually attributable to HPA-la antibodies. We report a case of parental platelet antigen incompatibility associated with a severe neonatal thrombocytopenia secondary to alloimmunization to HPA-3a. MATERIALS AND METHODS: Platelet antibodies were detected by the monoclonal antibody-specific immobilization of platelet antigens, genotyping of the platelets by PCR, and HLA typing by serologic procedures and PCR. RESULTS: Genotyping of maternal and paternal platelets confirmed the incompatibility in the HPA-3a system. It is noteworthy that the mother is of the HLA type DRB3*0101, is ABO-incompatible with her husband, and also has HLA class I antibodies. CONCLUSION: Severe neonatal thrombocytopenia associated with HPA-3a alloimmunization is infrequent and all the factors mentioned above could have played a role in the severity of the disease.

The role of the fetal immune system in the pathogenesis of RhD-hemolytic disease of newborns.

Data in the literature and author's research regarding the role of the immune reaction of fetuses and newborns in the pathogenesis of RhD conflict and hemolytic disease of newborns was analyzed. In this disease, the immune response of fetuses and newborns is shown to develop under the effects of maternal antigens, including RhD IgG, which cross the placenta. One of the results is the formation of immune complexes (ICs) between the maternal antigens and fetal IgM. In the intensive immune reaction, these ICs are removed from the infants at a high rate. As a result, the intensity of erythrocyte destruction, the degree of anemia and hyperbilirubinemia decrease. Various forms of HDN are of different intrauterine duration: from a few days in the icteric form without anemia to a month or more, in the hydropic form. In the latter form, decompensation of the immune system develops; extravascular erythroclasia by macrophages is replaced by intravascular lysis of erythrocytes. We suggest some methods to determine the fetal condition and a cure for the most severe cases of HDN, as well as a way of decreasing RhD-sensitization in women. These suggestions may be of interest to specialists in pediatrics and obstetrics and may be of clinical use.

Carboxyhemoglobin levels in neonatal immune hemolytic jaundice treated with intravenous gammaglobulin.

In order to examine the effect of intravenous immunoglobulin (IVIG) on the rate of hemolysis in immune hemolytic hyperbilirubinemia, we measured the carboxyhemoglobin levels of 5 newborn infants who were subjected to IVIG treatment. The pretreatment rate of hemolysis, in the 5 patients with isoimmune hemolytic jaundice (3 patients with Rh hemolytic disease of the newborn and 2 patients with ABO hemolytic disease of the newborn), as reflected by carboxyhemoglobin levels was higher than the rate of hemolysis in normal newborn infants. In 4 out of the 5 patients treated with IVIG, there was a rapid decline ( > 30%) of carboxyhemoglobin levels, a pattern which was different from that observed in normal newborn infants with no hemolytic jaundice and in 3 untreated patients with ABO hemolytic disease of the newborn. None of the treated patients required an exchange transfusion. Our preliminary results support the theory that the attenuation of jaundice observed following IVIG treatment in patients with immune hemolytic hyperbilirubinemia is caused, at least in part, by the reduction in hemolysis.

The Le(a) antigen and neonatal hyperbilirubinemia in Taiwan.

Neonatal jaundice is known to be more severe in Taiwanese infants than in Caucasian infants. Although ABO fetomaternal incompatibility and glucose-6-phosphate dehydrogenase deficiency have been shown to play a role in the etiology of neonatal jaundice in some Taiwanese infants, the etiology in the majority of cases is unknown. In this study we found that in Taiwanese newborn infants, the red cell Le(a) antigen appeared later in infants who were jaundiced (peak serum bilirubin levels of > 12 mg/dl during the first week of life) than in infants who were not. However, the Leb antigen, and hence the transferase encoded by the Se and Se(w) genes, did not appear to be similarly involved in the etiology of physiological jaundice. Thus it would appear that the Le gene-specified transferase is less active or has a delayed function, in jaundiced infants. The relationship between the Le gene-specified transferase and bilirubin has yet to be established.

Pure anti-Doa stimulated by pregnancy.

Pure anti-Doa stimulated by pregnancy was detected in 2 non-transfused females during routine antenatal screening. Anti-Doa occurs rarely and has generally been reported in combination with other antibodies. The first, and only report to date, of pure anti-Doa was also stimulated by pregnancy. We believe these instances to be only the second and third reported cases of pure anti-Doa.

[Clinical and immune hematologic problems in prenatal prevention of Rhesus sensitization]. / Klinische und immunhämatologische Probleme mit der antenatalen Prophylaxe der Rhesus-Sensibilisierung.

Various studies have provided impressive evidence of the efficacy of antenatally administered anti-D in the prevention of rhesus (D) alloimmunisation in rhesus-negative women. However, possible clinical and immunohaematological problems associated with this prophylactic therapy have received little attention. We describe perinatal and immunohaematological problems, which occurred in four cases after antenatal rhesus prophylaxis. Classical immunohaematological techniques were employed, to detect and specify irregular red cell antibodies. It was found, that the antenatal administration of anti-D could mask sensitization to other red cell antigens or the production of maternal immune anti-D antibodies later in pregnancy. A further problem encountered was that of neonates with a positive direct Coombs' test (the uncertainty in the individual case being, whether this is a result of the antenatal administration of anti-D) and marked hyperbilirubinaemia. Antenatal immunoprophylaxis for rhesus disease can give rise to immunohaematological and clinical findings, of which the interpretation is extremely difficult and requires intensive cooperation between the obstetrician, neonatologist, and haematologist/clinical biochemist.

[The interrelationship between the O2-dependent bactericidal mechanism and hyperbilirubinemia of newborn].

In order to investigate the influence of indirect bilirubin to O2-dependent bactericidal mechanism in adult and newborn phagocytes we use the NBT reduction activity of granulocytes and monocytes as index, by infiltrated granulocytes and monocytes in different concentration of indirect bilirubin with or without latex stimulator. The NBT reduction activity of granulocytes infiltrated in 20 mg/dl indirect bilirubin will increase slightly, compared to uninfiltrated; but with latex stimulator, the increment will decrease significantly, this change is reversible, when indirect bilirubin be washed, the stimulating capacity by latex stimulator in granulocyte will be stronger; there were no such change pattern in monocytes. Since there were a big difference in NBT reduction activity of granulocytes and monocytes between newborns, with or without latex stimulator, we can't get a satisfied result. Indirect bilirubin in cells will increase NBT reduction activity of monocytes, but not in granulocytes.