The Clinical Spectrum of ABO Incompatibility and Hemolytic Disease in the Newborn

Abstract Abstract 1182 Introduction: ABO hemolytic disease of the newborn occurs almost exclusively in infants of blood group A or B who are born to group O mothers. Although ABO incompatibility is common, its related hemolytic disease has been reported to be low. In this study, we aimed to investigate the rate of direct anti-globulin test (DAT) positivity and clinical events, such as hyperbilirubinemia or anemia in infants born to group O mothers. Methods: Using the charge code for cord blood evaluation, we were able to identify all cord blood evaluations from January 1, 2006 - December 31, 2007, and then select out the ABO incompatible births from group O mothers. We then reviewed the electronic medical records for demographic, clinical and laboratory information. Clinical events (anemia, jaundice, hemolytic disease) were investigated only in babies born at 37 weeks or higher gestation. Chi-square tests were used to cross-tabulate clinical events, demographic parameters (gender, ethnicity), and laboratory parameters (AO versus BO incompatibility, DAT-positivity). Results: There were 10,891 live births during the two-year period and 1519 (14%) of these were ABO incompatible. ‘Black’ ethnicity was registered in 80% of these babies. AO and BO incompatibility comprised 57.8% and 42.2% of the cases, respectively. 5.3% of the cases had concomitant Rh incompatibility. DAT was positive in 16.7% of the cases: 13.8% weakly or 1+ positive, and 2.9% 2+ or 3+ positive. DAT was more commonly positive among BO-incompatible cases compared to AO-incompatible cases (21.7% versus 13.1%). Among blacks, DAT-positivity in BO incompatibility was more common (24.9% among blacks compared to 7.8% among non-blacks, p<0.001). Concomitant Rh incompatibility did not affect DAT positivity rate. Among AO-incompatible babies, DAT-positivity was more frequent among females (15.5% in females vs 10.8% in males, p=0.045). 1299 babies were born at term (3 37 weeks gestation).of these infants, hyperbilirubinemia (defined as indirect bilirubin 3 8 mg/dL) was detected in 17.3% of babies. This was significantly associated with DAT positivity (40.6% in DAT-positive cases vs 12.3% in DAT-negative cases, p<0.001) and BO incompatibility (p=0.001). Hemolytic anemia (defined as hematocrit £ 45% and reticulocyte count 3 250,000/mm3 in the first week of life) was noted in 3.4% of cases, and was significantly associated with DAT positivity (13.2% in DAT-positive cases vs 1.1% in DAT-negative cases, p<0.001); BO incompatibility (p=0.001); and black ethnicity (p=0.001). Discussion: Our study indicated that cord blood DAT was positive in 16.7% of ABO incompatible pregnancies. BO-incompatible cases were more likely to be DAT-positive in blacks. AO-incompatibility was more common among girls, consistent with earlier studies that had shown a stronger A antigen expression among female newborns. DAT-positive cases were more likely to develop hyperbilirubinemia or hemolytic anemia. In addition, black ethnicity and BO incompatibility conferred significantly increased risk of hemolytic anemia in our study. Despite this strong association, the sensitivity of the positive DAT was 41.3% for hyperbilirubinemia and 70.5% for hemolytic anemia in ABO incompatibility. Disclosures: No relevant conflicts of interest to declare.

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Letter to the Editor

PEDIATRICS ◽

10.1542/peds.50.1.169a ◽

1972 ◽

Vol 50 (1) ◽

pp. 169-169

Author(s):

Jane Desforges

Keyword(s):

Red Cells ◽

Hemolytic Disease ◽

Left Behind ◽

Abo Incompatibility ◽

Letter To The Editor ◽

Rh Incompatibility

In hemolytic disease, it is always difficult to comment on the properties of red cells which have already been removed from the circulation. One can only study those left behind and presumably, therefore, less injured. However, with the mechanism of immunohemolysis in Rh incompatibility as a prototype, one can propose hemolytic disease of the newborn in ABO incompatibility to be related to a coating antibody which is not complement dependent, rather than to the hemolysin.

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Phototherapy for Hyperbilirubinemia of Hemolytic Disease of the Newborn

PEDIATRICS ◽

10.1542/peds.75.2.407 ◽

1985 ◽

Vol 75 (2) ◽

pp. 407-441

Author(s):

Harold M. Maurer ◽

Barry V. Kirkpatrick ◽

Nancy B. McWilliams ◽

David A. Draper ◽

Dolores A. Bryla

Keyword(s):

Birth Weight ◽

Serum Bilirubin ◽

Hemolytic Disease ◽

Bilirubin Concentration ◽

Term Infants ◽

Abo Incompatibility ◽

Rh Incompatibility ◽

Infant Birth ◽

Positive Results ◽

Serum Bilirubin Concentration

Although phototherapy has proven effective in lowering the serum bilirubin concentration of fullterm and premature infants with physiologic or idiopathic hyperbilirubinemia, its effect on serum bilirubin concentration in hemolytic disease due to ABO blood group incompatibility remains uncertain. Sisson and associates91 have reported a marked effect of phototherapy on serum bilirubin levels and exchange transfusion rates in premature and full-term infants with ABO incompatibility. Others have reported similar findings, but studies were retrospective49 or uncontrolled.80 On the other hand, Patel and associates79 found no significant clinical response to phototherapy in five infants (four with birth weight >2,500 g) with ABO and one infant (birth weight 2,660 g) with Rh incompatibility. A total of 1,339 infants were randomly selected for study between May 1974 and June 1976. Of the 1,339 infants, 79.4% weighed less than 2,500 g and 276 (20.6%) were 2,500 g or more at birth. Of the 1,063 infants who weighed less than 2,500 g, 17 had positive findings on Coombs tests, 14 due to ABO incompatibility and three due to Rh incompatibility. As phototherapy was administered early and prophylactically in infants weighing less than 2,000 g and late and therapeutically in infants weighing between 2,000 and 2,499 g, a combined analysis of the infants weighing less than 2,500 g and who had positive results on Coombs test was not possible. Of the 276 infants whose birth weight was 2,500 g or more, 64 (23.1%) had positive findings on Coombs tests, 58 due to ABO incompatibility and six to Rh incompatibility.

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Polyclonal Anti-Kel (KELGAM) Prevents Alloimmunization to Transfused Kel RBCs in a Murine Model

Blood ◽

10.1182/blood.v124.21.758.758 ◽

2014 ◽

Vol 124 (21) ◽

pp. 758-758

Author(s):

Sean R. Stowell ◽

Connie M Arthur ◽

Kathryn R. Girard-Pierce ◽

Harold Clifford Sullivan ◽

Manjula Santhanakrishnan ◽

...

Keyword(s):

Conflicts Of Interest ◽

Antigen Expression ◽

Transgenic Mouse Model ◽

In Vitro Testing ◽

Immune Deviation ◽

Hemolytic Disease ◽

Control Groups ◽

First Time ◽

Rbc Transfusion

Abstract Introduction: Polyclonal anti-D preparations are among the most successful prophylactic immunotherapies in existence today. The mechanism(s) of action of polyclonal anti-D are not well understood, and no monoclonal therapy developed to date has been as effective as polyclonal preparations at preventing pregnancy associated RhD sensitization. Furthermore, no prophylactic therapies exist to prevent alloimmunization to non-RhD antigens. We have recently developed a transgenic mouse model of RBC alloimmunization to KEL, with sensitization to KEL occurring through pregnancy as well as through transfusion. We hypothesized that polyclonal anti-KEL (“KELGAM”) would prevent KEL RBC alloimmunization, and herein test this hypothesis in a controlled transfusion setting. Materials and Methods: Polyclonal anti-KEL (KELGAM) was generated in IgHa congenic mice following repeat transfusions of transgenic KEL RBCs. This polyclonal anti-KEL was then passively infused into naïve C57BL/6 (IgHb) mice, at a dose that led to maximal clearance of KEL RBCs. 50 microliters of lipophilically labeled KEL RBCs were transfused into these passively immunized mice, with evaluation by flow cytometry of anti-KEL RBC binding, complement positivity, transfused RBC clearance, and active recipient anti-KEL responses. Controls included animals transfused in the absence of passively infused anti-KEL, animals given a 3rd party polyclonal antibody prior to KEL RBC transfusion, and animals given anti-KEL but transfused with RBCs expressing a 3rdparty RBC antigen. 16 weeks post-transfusion, animals initially treated with or without KELGAM prior to KEL RBCs were transfused again with KEL RBCs, with responses compared to that of naïve animals. Results: In 3 of 4 experiments (n=3-5 mice/group/experiment), mice treated with IgHa KELGAM prior to KEL RBC transfusion generated no detectable anti-KEL glycoprotein IgHb alloantibodies by 4 months post-transfusion. In contrast, 100% of control mice transfused with KEL RBCs in the absence of KELGAM or transfused with KEL RBCs in the presence of a 3rdparty antibody generated anti-KEL glycoprotein IgHb alloantibodies (adjusted MFI >100 using sera at a 1:2 dilution). Approximately 50% of DiI labeled KEL RBCs cleared within 24 hours in the KELGAM group, whereas KEL RBCs didn’t begin clearing in the control groups until 5-7 days post-transfusion at which time the recipients began to generate anti-KEL. The DiI labeled KEL RBCs had surface bound IgG and C3b until 24 hours post-transfusion, after which time neither bound antibody, C3b, nor KEL antigen could be detected. In contrast, DiI labeled KEL RBCs in the control groups had detectable KEL antigen on their surface until 5 days post-transfusion, at which time the recipients began to generate anti-KEL. Animals initially treated with KELGAM prior to transfusion were able to generate anti-KEL upon a second exposure to KEL RBCs 4 months later, with similar responses to naïve animals seeing KEL RBCs for the first time. Conclusions: Polyclonal anti-KEL (KELGAM) effectively eliminates primary anti-KEL glycoprotein alloantibody responses to transfused KEL RBCs. However, the mechanism of action of KELGAM may be different from that of polyclonal anti-D. The dose of KELGAM used for these studies saturates all detectable KEL antigen sites on the transfused RBCs. Distinct from what has been described with polyclonal anti-D, the transfused RBCs remaining in circulation from 24 hours after KELGAM treatment until day 28 post-transfusion modulate KEL antigen expression such that they no longer bind to KELGAM during in vitro testing. Furthermore, the addition of an excess of KELGAM does not lead to KEL RBC clearance rates beyond 50%. KELGAM transfusion recipients are not tolerized to the KEL antigen, as re-challenge with KEL RBCs months later leads to robust anti-KEL responses. Ongoing studies are further investigating whether KELGAM recipients may experience antibody mediated immune deviation, whether KELGAM is capable of suppressing responses to other antigens co-expressed on the same RBC, and whether KELGAM is effective at eliminating pregnancy induced anti-KEL alloimmunization. A goal of these studies includes the eventual translation of this knowledge to the setting of hemolytic disease of the fetus and newborn in humans. Disclosures No relevant conflicts of interest to declare.

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Impact Of ABO Incompatibility On Overall Survival After Unrelated Cord Blood Transplantation a Single Institute Experience In China

Blood ◽

10.1182/blood.v122.21.5535.5535 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5535-5535

Author(s):

Sun Zimin ◽

Ji Mengmeng ◽

Yao Wen ◽

Zheng Changcheng ◽

Tong Juan ◽

...

Keyword(s):

Cord Blood ◽

Clinical Outcomes ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Disease Free Survival ◽

Pure Red Cell Aplasia ◽

Blood Transplantation ◽

Abo Incompatibility ◽

Transfusion Requirements ◽

The Impact

Abstract Umbilical cord blood transplantation (UCBT) has now become a more common treatment for patients with hematologic malignancies who lack matched related or unrelated donors. However, few reports have addressed the impact of ABO incompatibility on the clinical outcomes, such as engraftment, transfusion requirements and survival after UCBT. Therefore, we retrospectively analyzed the impact of ABO mismatching on the clinical outcomes of 121 patients, including 51 ABO-identical, 23 minor, 39 major, and 8 bidirectional ABO-incompatible recipients after UCBT. With a median follow-up of 11 months (range, 5-151 months), the disease-free survival (DFS) rates among the ABO-identical, minor, major, and bidirectional ABO-incompatible groups were 71.7%, 60.0%, 37.1%, and 71.4%, respectively (P=0.014), whereas the OS did not differ significantly among the four groups (76.1%, 65.0%, 48.6%, and 71.4%, respectively; P=0.078). The DFS (68.2%, 42.9%; P=0.009) and OS estimates (72.7%, 52.4%; P=0.031) of the ABO identical/minor incompatible group also differed significantly from the ABO major/bidirectional incompatible group. These results were confirmed in the multivariate analysis. No signiﬁcant differences in the engraftment times, transfusion requirements, graft-versus-host disease (GVHD), relapse, and non-relapse mortality (NRM) were noted among the groups. Severe immune hemolysis or pure red cell aplasia did not occur among these patients. These results indicate that ABO incompatibility somewhat affects the DFS and OS in UCBT, but further studies are still required. Disclosures: No relevant conflicts of interest to declare.

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ABO Incompatibility in the Newborn

Journal of Neonatology ◽

10.1177/0973217919908368 ◽

2019 ◽

Vol 33 (1-4) ◽

pp. 22-25

Author(s):

Chelsey Kimball

Keyword(s):

Exchange Transfusion ◽

Close Monitoring ◽

Hemolytic Disease ◽

Benign Condition ◽

Common Cause ◽

Low Level ◽

Abo Incompatibility ◽

Rh Incompatibility ◽

Common Manifestation ◽

Antenatal Treatment

ABO incompatibility is one form of hemolytic disease of the newborn (HDN). Since the development of antenatal treatment for Rh incompatibility has developed, ABO incompatibility has emerged as the most common cause of HDN. Generally, ABO incompatibility is a benign condition because of the low level of hemolysis that occurs. Infants with ABO incompatibility do require close monitoring and treatment, based on the symptoms. The most common manifestation of ABO incompatibility is hyperbilirubinemia. This hyperbilirubinemia can usually be managed effectively with conventional measures such as phototherapy. However, rare complications such as anemia and, in extreme cases, kernicterus may require blood or exchange transfusion.

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Mechanisms of Resistance to Lenalidomide in Del(5q) Myelodysplastic Syndrome Patients

Blood ◽

10.1182/blood.v126.23.5228.5228 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5228-5228 ◽

Cited By ~ 2

Author(s):

Sergio Martinez-Høyer ◽

Rod Docking ◽

Simon Chan ◽

Martin Jadersten ◽

Jeremy Parker ◽

...

Keyword(s):

Stem Cell ◽

Molecular Mechanisms ◽

De Novo ◽

Conflicts Of Interest ◽

Strong Association ◽

Tp53 Gene ◽

Hematopoietic Stem ◽

Tp53 Mutations ◽

Paired Samples ◽

Increased Risk

Abstract Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem/progenitor cell malignancies characterized by the presence of dysplastic bone marrow (BM) cells leading to inefficient hematopoiesis in one or more myeloid lineages. The most common chromosomal alteration in MDS, accounting for ~20% of cases, is defined by interstitial deletion of the long arm of chromosome 5, and these cases comprise a distinctive subtype in MDS termed del(5q) . Patients suffering from del(5q) MDS present with anemia, variable neutropenia and thrombocytosis. Patients are blood transfusion dependent, which over time can lead to high mortality due to iron overload. The immunomodulatory drug lenalidomide (LEN) is the treatment of choice for del(5q) patients, achieving transfusion independence and remission in two thirds of treated patients. At the molecular level, LEN cytotoxic activity relies on its binding to the E3-ligase adaptor cereblon (CRBN) selectively leading to CSNK1a protein degradation. Unfortunately, 50% of patients eventually acquire resistance and relapse 2 to 3 years after treatment. Of note, patients at relapse present an increased risk to progress to acute myeloid leukemia. Mutations in the TP53 gene are correlated with resistance to LEN in del(5q) MDS. However, only approximately 20% of patients that become resistant are TP53 mutated. Therefore, there is a medical need to identify drivers of resistance to LEN in del(5q) patients in order to design patient tailored therapies and prevent relapse episodes. To this end, we have collected CD34+ cells from the BM of six del(5q) MDS patients at the time of diagnosis and upon relapse after treatment with LEN and performed whole genome and transcriptome sequencing on these paired samples. By comparing the genome sequencing data at the two time points, we have identified two patients harboring mutations in the TP53 gene: TP53 R273S arises de novo at the resistant stage and TP53 C106Y is existing at diagnosis and expands at relapse. These results are in accordance with previous reports showing strong association of TP53 mutations and resistance to LEN and therefore validate our approach. In addition, we have identified candidate mutations as drivers of the resistant phenotype, which we hypothesize may substitute or cooperate with TP53 mutations, allowing for the malignant del(5q) stem cell survival during LEN treatment and expansion at relapse. Furthermore, RNA-seq data analysis from the paired samples has identified differentially expressed genes shared among all resistant cases and led us to identify novel putative pathways leading to resistance to LEN in del(5q) hematopoietic stem cell. Of note, we did not find any mutation or significant change in the expression of CRBN or CSNK1A1 genes in our cohort of del(5q) MDS patients at relapse, and therefore they do not have a prognostic value for resistance to LEN. The integration of the data obtained in our study will shed light in to the molecular mechanisms leading to resistance to LEN in del(5q) MDS patients and may pave the way for the design of novel and more effective therapies to treat these patients at relapse. Disclosures No relevant conflicts of interest to declare.

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SPHEROCYTOSIS AND INCREASED FRAGILITY OCCURRING IN ERYTHROBLASTOSIS FETALIS ASSOCIATED WITH ABO INCOMPATIBILITY

PEDIATRICS ◽

10.1542/peds.7.2.164 ◽

1951 ◽

Vol 7 (2) ◽

pp. 164-171

Author(s):

GEOFFREY C. ROBINSON ◽

RUTH M. PHILLIPS ◽

MILTON PRYSTOWSKY

Keyword(s):

Hemolytic Anemia ◽

Antibody Titre ◽

Newborn Infant ◽

Diagnostic Value ◽

Hemolytic Disease ◽

Abo Incompatibility ◽

Immune Antibody

Four cases of hemolytic disease of the newborn infant are reported. There was ABO incompatibility and high maternal immune antibody titre after delivery. Immune antibody was demonstrated in the sera of 3 of the 4 infants. The difficulties in making an unequivocal diagnosis are discussed and the diagnostic value of immune antibody in the infant's serum is emphasized. The presence of spherocytosis and altered erythrocyte hypotonic fragility during the hemolytic phase is noted. These findings are similar to cases of acute hemolytic anemia in adults previously reported.

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Phototherapy in Full-Term Infants with Hemolytic Disease Secondary to ABO Incompatibility

PEDIATRICS ◽

10.1542/peds.74.3.371 ◽

1984 ◽

Vol 74 (3) ◽

pp. 371-374

Author(s):

Lucy M. Osborn ◽

Carl Lenarsky ◽

Raymond C. Oakes ◽

Michael I. Reiff

Keyword(s):

Exchange Transfusion ◽

Full Term ◽

Hemolytic Disease ◽

Term Infants ◽

Abo Incompatibility ◽

Rh Incompatibility ◽

Current Guidelines ◽

Observation Period

Current guidelines for treatment of hemolytic disease of the newborn make no differentiation between ABO and Rh incompatibility. A protocol that prolonged the observation period in full-term, ABO-incompatible infants with positive Coombs' tests who were otherwise healthy was tested. Postponement of treatment made it possible to determine more accurately which infants needed phototherapy. This dramatically decreased the number of infants treated without increasing their risk of requiring exchange transfusion.

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Short- and long-term outcomes of preterm spontaneous twin anemia-polycythemia sequence

Journal of Perinatal Medicine ◽

10.1515/jpm-2019-0437 ◽

2020 ◽

Vol 48 (4) ◽

pp. 329-334

Author(s):

Soo Jin Han ◽

Seung Mi Lee ◽

Sohee Oh ◽

Subeen Hong ◽

Jeong Won Oh ◽

...

Keyword(s):

Cord Blood ◽

Neonatal Morbidity ◽

Adverse Outcomes ◽

Control Group ◽

Long Term Outcomes ◽

Neurodevelopmental Outcomes ◽

Monochorionic Twin ◽

Increased Risk ◽

Study Population

AbstractBackgroundIn monochorionic twin pregnancy, placental anastomosis and inter-twin blood transfusion can result in specific complications, such as twin-twin transfusion syndrome (TTTS) and twin anemia-polycythemia sequence (TAPS). It is well established that adverse outcomes are increased in TTTS, but reports on the neonatal and long-term outcomes of TAPS are lacking. The objective of this study was to evaluate the neonatal and neurodevelopmental outcomes in spontaneous TAPS.MethodsThe study population consisted of monochorionic twin pregnancies with preterm birth (24–37 weeks of gestation) between November 2003 and December 2016 and in which cord blood was taken at the time of delivery. According to the result of hemoglobin in cord blood, the study population was divided into two groups: a spontaneous TAPS group and a control group. Neonatal and neurodevelopmental outcomes were compared between the two groups.ResultsDuring the study period, 11 cases were diagnosed as spontaneous TAPS (6.4%). The TAPS group had lower gestational age at delivery and had a higher risk for cesarean delivery. However, neonates with TAPS were not at an increased risk for neonatal mortality and significant neonatal morbidity. In addition, the frequency of severe cerebral lesion during the neonatal period and the risk of cerebral palsy at 2 years of age were not different between the two groups.ConclusionThe spontaneous TAPS diagnosed by postnatal diagnostic criteria was not associated with the increased risk of adverse neonatal and neurodevelopmental outcomes. Further studies are needed to evaluate the morbidity of antenatally diagnosed TAPS.

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Severe Acute Respiratory Syndrome Coronavirus 2 Placental Infection and Inflammation Leading to Fetal Distress and Neonatal Multi-Organ Failure in an Asymptomatic Woman

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piaa153 ◽

2020 ◽

Author(s):

Sam Schoenmakers ◽

Pauline Snijder ◽

Robert M Verdijk ◽

Thijs Kuiken ◽

Sylvia S M Kamphuis ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Vertical Transmission ◽

Neonatal Intensive Care ◽

Quantitative Polymerase Chain Reaction ◽

Antigen Expression ◽

Fetal Distress ◽

Adverse Outcomes ◽

Placental Infection ◽

Emergency Cesarean ◽

Increased Risk

Abstract Background In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood. Methods Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy. Results RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts. Conclusions Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic.

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