Prediction of ABO hemolytic disease of the newborn using pre- and perinatal quantification of maternal anti-A/anti-B IgG titer.

BACKGROUND: Hemolysis in fetus/newborns is often caused by maternal antibodies. There are currently no established screening procedures for maternal ABO antibodies harmful to fetus/newborn. We investigated the clinical significance, and predictive value of maternal anti-A/B titer for hyperbilirubinemia in ABO-incompatible newborns. METHODS: We conducted a case-control study of blood group O mothers and their ABO-compatible (O) vs. -incompatible (A/B) newborns receiving phototherapy, and of ABO-incompatible newborns receiving phototherapy vs. no phototherapy. Newborn data and treatment modalities were recorded, and total serum bilirubin and hemoglobin were measured. Maternal anti-A/B immunoglobulin-γ (IgG) titers were measured prenatally and perinatally, and negative and positive predictive values (NPV, PPV) were calculated to assess the risk of developing hyperbilirubinemia requiring phototherapy. RESULTS: We found a significantly higher maternal IgG antibody titer in the case group (p < 0.001). Maternal anti-A/B titers at first trimester had modest predictive values: NPV = 0.82 and PPV = 0.65 for neonatal hyperbilirubinemia; titers at birth improved the predictive values: NPV = 0.93 and PPV = 0.73. Newborn hemoglobin was significantly lower in incompatibles compared to compatibles (p = 0.034). Furthermore, increased anti-A/B IgG production during pregnancy was associated with hyperbilirubinemia and hemolysis in incompatible newborns. CONCLUSIONS: There was a significant association between maternal anti-A/B IgG titer and hyperbilirubinemia requiring treatment. IMPACT: Maternal anti-A/B IgG titer in the first trimester and at birth is predictive of hemolytic disease of the ABO-incompatible newborn. Increased IgG anti-A/B production throughout pregnancy in mothers to ABO-incompatible newborns developing hyperbilirubinemia contrasts a constant or reduced production in mothers to newborns not developing hyperbilirubinemia. Screening tools available in most immunohematology laboratories can identify clinically important IgG anti-A/B. Use of maternal samples taken at birth yielded NPV = 0.93 and PPV = 0.73.

ABO hemolytic disease of newborn : Does newborn's blood group a risk factor?

BACKGROUND: Due to the marked decline of maternal-fetal rhesus incompatibility, ABO alloimmunization has become the leading cause of the newborn hemolytic disease. It is estimated that 15-25 % of all pregnancies are concerned by ABO incompatibility. AIM: Neonatal blood group B seems to be more predisposing to acute hemolysis and severe hyperbilirubinemia. We propose to find if the newborn's blood group B represents a risk factor for severe hemolysis and/or severe hyperbilirubinemia. METHODS: We conducted a comparative study in the pediatrics department "B" of the Children Hospital of Tunis. We collected retrospectively the medical files of the newborn hospitalized for ABO alloimmunization (January 2011 - March 2014), then we compared two groups, OA group with OA alloimmunization and OB group with OB alloimmunization. A significant threshold was fixed to 0.05. RESULTS: We collected 98 cases of newborn ABO hemolytic disease. Both groups, OA and OB, were similar for the onset of jaundice, age of hospitalization, initial hemoglobin and indirect bilirubin levels. There were no statistically significant difference in the severity of hyperbilirubinemia and the use of exchange transfusion for the two groups. However, transfusion was statistically more frequent in the OB group compared to OA group (81.6‰ vs 10.2‰, p = 0,039, OR=2.9, 95% IC (1.1 - 7.8)). CONCLUSION: OB alloimmunization seems to induce more active hemolysis than OA one, with no difference for severe hyperbilirubinemia in both groups.

Revisiting ABO incompatibility as a risk factor for significant neonatal hyperbilirubinemia.

Babies with ABO incompatibility are often advised frequent biochemical screening and prolonged hospital stay. Our primary objective of the study was to compare serum bilirubin levels at 48 h and 96 h of age in neonates with and without ABO incompatibility. Our prospective study included neonates with gestation ≥ 34 weeks, with or without ABO incompatibility (92 in each group). A direct Coombs test was performed on cord blood. The mean serum bilirubin and haematocrit levels in both groups at 48 h and 96 h were comparable. The mean reticulocyte count of babies with ABO incompatibility was, however, significantly higher. Late preterm and term neonates with and without ABO incompatibility have similar bilirubin levels and no increased risk of significant hyperbilirubinemia. Prolonged hospitalisation of these neonates appears to be unnecessary.

Neonatal hyperbilirubinemia secondary to combined anti e and anti C isoimmunisation: a literature review.

A term male infant was admitted at 48 h of postnatal life to the neonatal unit for jaundice. The investigation showed total serum bilirubin (TSB) of 17.1 mg/dl, haemoglobin of 11 g/dl, reticulocyte count of 9.5% and peripheral smear was suggestive of macrocytic, normochromic red blood cell (RBC) with target cells and multiple spherocytes with occasional nucleated RBC. The infant's blood group was B positive. Direct antiglobulin test was strongly positive by gel method (3+). Mother's blood group was B positive and indirect antiglobulin test was positive when tested postnatally. Extended minor blood grouping and cross matching showed this as a case of combined anti e and anti C antibodies isoimmunisation. Infant was treated with phototherapy for 72 h and was shifted to mother side. Infant was serially monitored with TSB level every sixth hourly and American Academy of Pediatrics (AAP) phototherapy charts were followed to see for rebound hyperbilirubinemia. The neonate was discharged and there was no readmission for hyperbilirubinemia. It is very rare and we report the third case of its type till date.

Effect of Phototherapy on CD4, CD8 and Natural Killer Cells of Full Term Neonates with Indirect Hyperbilirubinemia.

Phototherapy is generally considered a very safe and well-tolerated treatment for hyperbilirubinaemia. However, clinical users should be aware of the unwanted effects of using phototherapy. Affection of neonatal immune system due to phototherapy has been reported. This study aimed to evaluate the effect of phototherapy on level of CD4+, CD8+ and natural killer (NK) (CD16+ & CD65+) lymphocytes subsets in neonates. The number of these lymphocytes was measured 72 hrs after phototherapy exposure in 30 full term neonates with indirect hyperbilirubinemia and compared to those of 25 healthy controls using flow cytometry. Results showed non-significant changes of the tested lymphocyte subsets after 72 hrs exposure to phototherapy. In conclusion, phototherapy has no significant effect on the level of circulating CD4+, CD8+ and NK lymphocytes.

[Management of feto-maternal red cell allo-immunizations]. / Prise en charge des allo-immunisations fœto-maternelles antiérythrocytaires.

Feto-maternal red cell alloimmunization is defined by the presence in a pregnant woman of alloantibodies directed against blood group antigens present on the red blood cells of the fetus and inherited from the father. It arises from the immune response to a first contact to these same antigens during a prior transfusion, transplant or pregnancy. The placental transfer and the fixation of the antibodies on the fetal red cells antigenic targets lead to a haemolysis in the fetus and the newborn. The resulting haemolytic disease can show different clinical forms, from a mild anaemia with neonatal hyperbilirubinemia to a major fetal damage with stillbirth caused by hydrops fetalis. The objective of management strategies of feto-maternal alloimmunization is to detect and monitor maternal alloimmunization and to appreciate the effects on the fetus or the newborn. Since a few years, some new non-invasive techniques of surveillance are used, for instance fetal RHD genotyping on maternal plasma and evaluation of fetal anaemia through velocimetry measurement of the blood flow in the middle cerebral artery. The need for a careful postnatal surveillance has to be emphasized due to the neonatal anaemia, which can be prolonged, and to the resurgence of cases of severe neonatal icteruses recently reported by the Académie de Médecine. The policy of prevention of anti-RH1 alloimmunization should also benefit from the evolution of biological techniques by allowing an improved targeting of concerned women.

Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID).

Adenosin deaminase (ADA) deficiency is the cause for Severe Combined Immunodeficiency (SCID) in about 15% of patients with SCID, often presenting as T (-)B (-)NK (-)SCID. Treatment options for ADA-SCID are enzyme replacement, bone marrow transplantation or gene therapy. We here describe the first patient with ADA-SCID and fatal hepatic failure despite bone marrow transplantation from a 10/10 HLA identical related donor. As patients with ADA-SCID may be at yet underestimated increased risk for rapid hepatic failure we speculate whether hepatitis in ADA-SCID should lead to the immediate treatment with enzyme replacement by pegylated ADA.

Congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease.

Neonatal lupus erythematosus is an uncommon disease caused by transplacental passage of maternal anti-Ro (SS-A), anti-LA (SS-B), or anti-U1RNP antibodies. Cutaneous findings of neonatal lupus are variable, but annular, erythematous plaques occurring within a few weeks of birth are most typical. Cutaneous lesions of congenital onset lupus erythematosus can differ from that of neonatal lupus erythematosus, presenting with atrophy or scarring, and less commonly, erosions. We report an unusual case of congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease.

[Trends in the diagnosis and management of neonatal hyperbilirubinaemia]. / Endring i diagnostikk og behandling av hyperbilirubinemi hos nyfødte.

BACKGROUND: The guidelines for diagnosis and treatment of neonatal hyperbilirubinaemia were changed at Vestfold Hospital, Norway in 1994 and 2007. Universal screening for ABO-immunization was implemented in 2006. This article describes effects of these changes. MATERIAL AND METHODS: Blood-type immunization, phototherapy and exchange transfusions were prospectively recorded in the 21-year period 1988-2008. Three cohorts comprised the basis for the analyses: infants born in the time-periods 1988-93, 1994-2006 or 2007-2008. RESULTS: 6.2 % of the infants born 1988-93 and 6.7 % born 1994-2006 received phototherapy. Physiological hyperbilirubinaemia in term infants was the main reason for phototherapy in the first cohort, while it was hyperbilirubinemia in preterm infants in the second cohort. 4.8 % of the infants born 2007-8 received phototherapy. Exchange transfusion was performed in 0.02 % born 1994-2008 and 0.2 % born 1988-93. Such transfusions were undertaken more frequently in cases with RhD-immunization (7.8 %) than in those with ABO-immunization (2.0 %). Universal screening for ABO-immunization increased the percentage of diagnosed cases in the population from 2.1 % to 3.6 %. No case of kernicterus was diagnosed. INTERPRETATION: Fewer term infants were treated with phototherapy for hyperbilirubinaemia after the changes of therapeutic guidelines in 1994, while more preterm infants were treated after this change. Far less exchange transfusions are performed nowadays than before 1994. ABO-immunization has been diagnosed more often after implementation of universal screening.

Maternal IgG anti-A and anti-B titres predict outcome in ABO-incompatibility in the neonate.

AIM: To evaluate predictors for risk of severe hyperbilirubinaemia and kernicterus in ABO-incompatible neonates with emphasize on maternal IgG anti-A/-B titres. METHODS: Blood group O women in labour at Oslo University Hospital, Ullevål, were included in the years 2004-2006. Offspring with blood group A or B had direct antiglobulin test performed and IgG anti-A/-B levels measured in maternal plasma. Blood group A or B infants developing severe hyperbilirubinaemia, received in addition to phototherapy, immunoglobulin treatment and/or exchange transfusion (EXT). RESULTS: Of 253 neonates, 61.3% had blood group O, 29.6% blood group A and 9.1% blood group B. Twenty neonates with blood group A or B received at least one immunoglobulin treatment. In multivariate analysis, maternal antibody-titres were the only significant predictors for immunoglobulin treatment (p < 0.0001), EXTs (p < 0.05) and duration of phototherapy (p < 0.0001). The need for invasive treatment increased sharply for antibody titres > or =512. Receiver operating characteristic analyses demonstrated that titres > or =512 had a sensitivity of 90% and a specificity of 72% for predicting immunoglobulin treatment and thus severe hyperbilirubinaemia. CONCLUSION: Maternal IgG anti-A/-B titres contribute to the prediction of risk of severe hyperbilirubinaemia in ABO-incompatible neonates, in addition to blood-grouping and direct antiglobulin-testing, especially following early discharge after delivery.

Severe neonatal hemolysis due to a maternal antibody to the low-frequency Rh antigen C(w).

C(w) is a low-frequency antigen in the Rh blood group system with a prevalence of approximately 2% in whites. Although anti-C(w) is not an uncommon antibody in pregnancy (0.1% incidence), clinically significant hemolytic disease of the newborn is highly unusual. We report the case of an infant with severe hyperbilirubinemia and persistent anemia due to a high-titer maternal C(w) antibody. The medical literature relating to maternal C(w) alloimmunization and neonatal outcome is also reviewed. In addition, recommendations are made regarding the management of pregnancies and newborns complicated by antibodies to C(w).

Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin.

During neonatal hyperbilirubinaemia, astrocytes activated by unconjugated bilirubin (UCB) may contribute to brain toxicity through the production of cytokines. As a first step in addressing the signal transduction cascades involved in the UCB-induced astroglial immunological response, we tested whether tumour necrosis factor (TNF)-alpha receptor 1 (TNFR1), mitogen-activated protein kinase (MAPK) and nuclear factor kappaB (NF-kappaB) would be activated in astrocytes exposed to UCB, and examined the profile of cytokine production. Astrocyte cultures stimulated with UCB showed a rapid rise in TNFR1 protein levels, followed by activation of the MAPKs p38, Jun N-terminal kinase1/2 and extracellular signal-regulated kinase1/2, and NF-kappaB. Interestingly, the induction of these signal effectors preceded the early up-regulation of TNF-alpha and interleukin (IL)-1beta mRNAs, and later secretion of TNF-alpha, IL-1beta and IL-6. Treatment of astrocytes with UCB also induced cell death, with levels comparable to those obtained after exposure of astrocytes to recombinant TNF-alpha and IL-1beta. Moreover, loss of cell viability and cytokine secretion were reduced when the NF-kappaB signal transduction pathway was inhibited, suggesting a key role for NF-kappaB in the astroglial response to UCB. These results demonstrate the complexity of the molecular mechanisms involved in cell injury by UCB during hyperbilirubinaemia and provide a basis for the development of novel therapeutic strategies.

[Effect of exanguinotransfusion on the immune system of neonate]. / Uticaj eksangvinotransfuzije na imunski sistem novoredjenceta.

Exanguinotransfusion is commonly used during therapeutic procedure in neonates with hyperbillirubinemia risking to cause brain injury of the neonate. This therapy without alternative may couse anemia, hyper or hypotonus, and behavior problems. Those disturbances are not clearly understood yet, but it appears that this process is mediated by the immune system. In order to confirm this hypothesis parallely with clinical examination, we performed the following laboratory investigations: red blood cell count, hemoglobin, hematocrite, white blood cells, natural killer cells, T lymphocyte subsets, ability of the peripheral blood phagocytes to reduce NBT, the phagocytic ability and hemiluminescent response. In the clinical examination the most common finding was hypertonus or hypotonus of the muscules. The values of hemoglobin and hematocrite were reduced, red blood cell count was similar, while the white blood cell particularly the monocyte count was increased compared to the control. The absolute number of T lymphocytes defined by CD2 and CD3 surface marker expression was depleted, while the number of DR positive cells as well as the number of NK cells was increased in group treated with exanguinotransfusion. We have also found an increase of NBT positive cells in the same group. There were no differences in the number of NBT positive cells, when they were prestimulated by PMA. Phagocytic ability was lower compared to the control, while hemiluminescent response was faster remaining on high level for a long time. All those differences remained for several months after exanguinotransfusion.

[Neonatal immune system changes caused by phototherapy]. / Promene u imunskom sistemu novoredjenceta izazvane fototerapijom.

It is noticed that phototerapy may cause disturbance in the behavior and higher incidence of infections in neonate. Moreover an electromagnetic radiation may influence different functions of cells. We examined the effects of pototherapy on the immune system of neonates applied because of hyperbilirubinemia. The examined healthy patients, without signs of infection, anoxia or birth injury. Physical examination, white blood cell count, surface differentiation markers on peripheral blood lymphocytes,and hemiluminescent response of peripheral blood leukocytes were performed before and immediately after phototerapy. Our results showed an increase in the total number of peripheral white blood cells: polymorphonuclears, lymphocytes and monocytes as well as a delay in the chemilumonescence response of the peripheral blood phagocytes with lower values of the pick, suggesting a decrease of their functional ability to respond by respiratory burst. This might be important in the case of bacteriemia when phothoterapy may complicate the existing infection. Those findings are temporary.