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Since the discovery of the Rh blood group system in 1940, a greater understanding of hemolytic disease of the fetus and newborn (HDFN) was gained. In the years thereafter, researchers and clinicians came to the current understanding that fetal and neonatal red blood cells (RBC) are hemolyzed by maternal alloantibodies directed against RBC antigens potentially leading to severe disease. Preventative measures, such as Rhesus(D) immunoprophylaxis (RhIG), have greatly decreased the prevalence of Rh(D)-mediated HDFN, although a gap between high-income countries and middle- to low-income countries was created largely due to a lack in availability and high costs of RhIG. Other important developments in the past decades have improved the identification, monitoring, and care of pregnancies, fetuses, and neonates with HDFN. Prenatally, fetal anemia may occur and intrauterine transfusions may be needed. Postnatally, pediatricians should be aware of the (antenatally determined) risk of hemolysis in RBC alloimmunization and should provide treatment for hyperbilirubinemia in the early phase and monitor for anemia in the late phase of the disease. Through this review, we aim to provide an overview of important historic events and to provide hands-on guidelines for the delivery and postnatal management of neonates with HDFN. Secondarily, we aim to describe recent scientific findings and evidence gaps. Conclusion : Multiple developments have improved the identification, monitoring, and care of pregnancies and neonates with HDFN throughout the centuries. Pediatricians should be aware of the (antenatally determined) risk of hemolysis in RBC alloimmunization and should provide treatment for hyperbilirubinemia in the early phase and monitor for late anemia in the late phase of the disease. Future studies should be set in an international setting and ultimately aim to eradicate HDFN on a global scale. What is Known: • Developments have led to a greater understanding of the pathophysiology, an improved serological identification and monitoring of at-risk cases and the current pre- and postnatal treatment. What is New: • This review provides the pediatrician with hands-on guidelines for the delivery and postnatal management of neonates with HDFN. • Future studies should be set in an international setting with the ultimate aim of eradicating HDFN.

Managing RhD-negative pregnancies is vital for preventing hemolytic disease of the fetus and newborn, which occurs when RhD-negative mothers develop anti-D antibodies after exposure to RhD-positive fetal blood. This retrospective cohort study evaluated the proportion of RhD-negative pregnancies and newborns in Japan by assessing current management practices and outcomes. This study included RhD-negative pregnant women who delivered at 22 weeks or later at 47 Japanese facilities between April 2018 and March 2023. Pregnancies with unknown newborn RhD status were excluded. Data were obtained from medical records. Among the 1088 RhD-negative women, 1062 met the inclusion criteria. RhD-negative pregnancies comprised 0.71% of the total cohort, with 8.7% RhD-negative newborns. Anti-D immunoglobulin was administered in 96.5% of pregnancies, with a maternal spontaneous sensitization rate of 0.6% before 28 weeks and no sensitization detected from 28 weeks to postpartum. Sensitized RhD-negative women had higher cesarean section, preterm delivery, and neonatal hemolytic anemia rates than the non-sensitized group, leading to increased neonatal intensive care unit admissions. Despite the low incidence of RhD-negative pregnancies, this study underscores the need for tailored management strategies, suggesting that non-invasive prenatal diagnosis of fetal RhD status could prevent unnecessary anti-D immunoglobulin administration, improving outcomes and resource utilization in Japan.

ABO blood type incompatibility hemolytic disease of newborn (ABO-HDN) and drug-induced immune hemolytic anemia (DIIHA) due to non-immunologic protein adsorption (NIPA) mainly cause extravascular hemolysis. All the reported severe DIIHA were caused by drug-induced antibodies, and rare report of acute intravascular hemolysis was caused by the NIPA mechanism or ABO-HDN. We report the first case of acute intravascular hemolysis induced by cefotaxime sodium - sulbactam sodium (CTX - SBT) in a case of ABO-HDN which resulted in death at 55 h after birth. The mother's blood type was O and RhD-positive, and the newborn's blood type was B and RhD-positive. No irregular red blood cell (RBC) antibodies or drug-dependent antibodies related to CTX or SBT was detected in the mother's plasma and the plasma or the RBC acid eluent of the newborn. Before the newborn received CTX - SBT treatment, the result of direct antiglobulin test (DAT) was negative while anti-B was positive (2 +) in both plasma and acid eluent. After the newborn received CTX - SBT treatment, the results of DAT for anti-IgG and anti-C3d were both positive, while anti-B was not detected in plasma, but stronger anti-B (3 +) was detected in acid eluent. experiments confirmed that NIPA of SBT promoted the specific binding of maternal-derived IgG anti-B to B antigen on RBCs of the newborn, thereby inducing acute intravascular hemolysis. The NIPA effect of SBT promoted the specific binding of mother-derived IgG anti-B in newborn's plasma to the newborn's RBC B antigens and formed an immune complex, and then activated complement, which led to acute intravascular hemolysis. Drugs such as SBT with NIPA effect should not be used for newborns with HDN.

The rare blood phenotype D−− is characterized by the absence of RhCcEe antigens. Women with this blood type who have experienced previous pregnancies may produce anti-Rh17 antibodies, which may cause severe fetal hemolytic anemia or fetal death in subsequent pregnancies. We report successful management of a pregnancy associated with fetal hemolytic disease owing to high titers of anti-Rh17 (1:4096) in a woman with a history of a pregnancy with fetal hydrops and intrauterine fetal death. During her second pregnancy, she received two sets of plasma exchange (PE) per week from weeks 12 till 20. Intrauterine transfusions (IUTs) were performed at 26, 27, 29, and 31 weeks. A male infant was born at 32 weeks and 4 days by normal vaginal delivery, with a birth weight of 1916 g (+ 0.16 SD). He received an exchange transfusion on day 0, immunoglobulin (intravenous immunoglobulin: 1 g/kg) on days 0 and 1, and photo therapy from days 0 to 6. He showed normal development without neurological abnormality and was discharged from the hospital on day 36. We successfully prevented complications caused by the presence of anti-Rh17 antibodies in the mother during pregnancy. The IUT and maternal PE may have promoted this favorable outcome.

RH1 incompatibility between mother and fetus can cause hemolytic disease of the fetus and newborn. In Switzerland, fetal RHD genotyping from maternal blood has been recommended from gestational age 18 onwards since the year 2020. This facilitates tailored administration of RH immunoglobulin (RHIG) only to RH1 negative women carrying a RH1 positive fetus. Data from 30 months of noninvasive fetal RHD screening is presented. Cell-free DNA was extracted from 7192 plasma samples using a commercial kit, followed by an in-house qPCR to detect RHD exons 5 and 7, in addition to an amplification control. Valid results were obtained from 7072 samples, with 4515 (64%) fetuses typed RHD positive and 2556 (36%) fetuses being RHD negative. A total of 120 samples led to inconclusive results due to the presence of maternal or fetal RHD variants (46%), followed by women being serologically RH1 positive (37%), and technical issues (17%). One sample was typed false positive, possibly due to contamination. No false negative results were observed. We show that unnecessary administration of RHIG can be avoided for more than one third of RH1 negative pregnant women in Switzerland. This reduces the risks of exposure to a blood-derived product and conserves this limited resource to women in actual need.

Background: For appropriate management of hemolytic disease of the fetus and newborn (HDFN), it is important to detect irregular red cell antibody in the antenatal period. Though it is a simple one-step method, it is not part of routine antenatal screening in many developing countries. To reiterate the importance of antenatal antibody screening, we have assessed the frequency and clinical significance of irregular red cell antibodies in our patient population. Materials and Methods: A prospective study was carried out from October 2013 to May 2015 at a tertiary care center from south India. All antenatal samples received by the laboratory for red cell antibody screening were screened using a commercial three-cell screening panel. Antibody identification along with further Immunohematological techniques as required were performed for cases with positive screening results. Neonates of the alloimmunized cases were followed up to determine the clinical significance of the antibody. Results: A total of 2336 antenatal mothers were screened for red cell antibodies. The overall rate of alloimmunization in the study group was 2.27%. Alloimmunization rate among RhD-negative pregnancies was 6.9%. Other than anti-D (49%), we identified anti-D + anti-C (5%), anti-G (5%), anti-c (5%), anti-E (2%), anti-e (2%), anti-H (Bombay phenotype) (7%), anti-M (2%), anti-Lea (2%), anti-Leb (12%), and autoantibodies (9%) in the maternal serum. Anti-D, anti-D + anti-C, anti-G, anti-c, and anti-H were found to be clinically significant in this study. Conclusion: This study showed that 1 in 125 RhD-positive pregnancies can develop red cell alloantibodies. Hence, implementing routine antenatal antibody screening irrespective of RhD status is essential.

Background: The main cause of hemolytic disease of the fetus and newborn (HDFN) is the incompatibility of the RHD antigen between mother and fetus. Following the discovery of cell-free fetal DNA (cffDNA), noninvasive fetal RHD genotyping also became possible, which will help in the better management of immunized RHD negative mothers and in the targeted prenatal injection of Rho(D) immune globulin (RhIG). The objective of this study was to establish a reliable method with high accuracy to determine the fetal RHD genotype. Methods: The project was a prospective observational cohort study. After cell-free DNA (cfDNA) extraction from maternal plasma, fetal RHD genotyping was performed by duplex real-time polymerase chain reaction (PCR) and exons 5, 7, and 10 of the RHD gene were examined. SRY and RASSF1A genes were used as internal controls to confirm the presence of cffDNA in maternal plasma. Results: Out of 40 samples, 33 were RhD positive heterozygous mothers and 7 cases were RHD negative. In three cases where both the fetal RHD and SRY genotypes were negative, RASSF1A was amplified in cell-free DNA sample treated with the BstUI enzyme, and the presence of cffDNA was confirmed. Conclusion: The findings reveal that the strategy used in this study is reliable and it is possible to determine the fetal RHD status with high accuracy. The strategy can help targeted injection of RhIG and prevent unnecessary injection in RhD negative mothers who carry an RhD negative fetus.

Introduction: Maternal red cell alloimmunization to Rh antigen in pregnant women occurs when the immune system is sensitized by foreign red blood cell surface antigens, in this case fetal red blood cells, inducing an immune response. Various antigens of blood group systems may cause alloimmunization, especially the Rh, Kel, Fy, JK, and MNS systems. This study aimed to determine alloimmunization to the different frequencies of Rh antigen among pregnant women in South Western Uganda. Methods: A total of 1369 pregnant women consented and were recruited into a cross-sectional study during their regular antenatal visits during the period August 2020 to July 2021. Samples (4 mL) of anticoagulated and coagulated blood were obtained, and Rh blood grouping including Rh antigen and the indirect antiglobulin test (IAT) was carried out using the agglutination technology of the LISS ID-Card technique in the Ortho Biovue ID-Micro Typing System. Results: Out of 1369 participants recruited to the study, 78 (5.7%) were [D.sup.-], 1291 were [D.sup.+], and 134 (9.8%) had alloantibodies. Among those with alloantibodies, 115 (85.8%) were [D.sup.+] and 19 (14.2%) [D.sup.-]. The percentage alloimmunization according to the Rh antigens was highest in e (9.72%), c (2.48%), C (2.34%) and E (0.94%) antigens. With the ABO system, alloimmunization was highest in blood group B (10.7%), followed by A (10.6%), O (9.2%) and then AB (7.1%). Alloimmunization was more prevalent in [D.sup.-] (24%) than in [D.sup.+] participants (8.9%). Rhesus antigen e was the most prevalent antigen (99.8%), followed by c. The alloimmunization rate of 9.8% among these participants is high, and appears in both [D.sup.+] and [D.sup.-] women. The other Rhesus antigens are seen to cause alloimmunization, with antigen e causing the highest prevalence. In conclusion, there is a need to identify antibodies and study the outcome for clinical significance, especially in [D.sup.+] women, to facilitate proper pregnancy management. Keywords: Rh alloimmunization, Rh antigens, hemolytic disease of the fetus and newborn, pregnant women, Western Uganda

ABO incompatibility and other alloantibodies have emerged as a significant cause of hemolytic disease of fetus and newborn (HDFN), leading to neonatal morbidity and mortality. We report three cases of severe ABO-HDFN where blood exchange transfusions (ETs) were required in neonates with hyperbilirubinemia. Blood grouping (ABO/RhD) was performed using conventional tube technique. The antibody screen was done using commercial three-cell panel (Bio-Rad ID-Diacell-I-II-III, Switzerland) by gel technique. Direct antiglobulin test (DAT) on neonatal sample and compatibility testing were also done by gel technique. Elution on DAT-positive sample was performed using \"heat elution\" method. All the three neonates were A RhD positive and were born to O RhD-positive mothers who were negative for antibody screen. Their DAT was positive (2+) and the elution of neonatal red cells yielded a positive reaction with A cells which was suggestive of anti-A antibody. The maternal anti-A (immunoglobulin G) antibody titers were high: 512 and 1024 (in two cases). The total serum bilirubin (mg/dl) of the three neonates was 22, 27, and 25 which came down significantly after they received ETs. Severe ABO-HDFN may occur in neonates born to mother with high titer ABO antibodies which can be effectively managed with ET.

Abstract Introduction/Objective Anti Diegoa antibody (DiA) is a rare antibody, associated with severe hemolytic disease of the newborn. It is seen in American Indians and Asians of Mongoloid descent. Only 2.6% of Hispanics and <0.01% of Caucasians and African Americans have this antibody, making it challenging to diagnose. We present a case of a DiA discovered accidentally. Methods/Case Report A 31-year-old G4P3 Hispanic female at 35 weeks 5 days of gestation presented with limited prenatal care and gestation complicated by chronic deep vein thrombosis, on enoxaparin. Her gestational history was significant for Anti-E Antibody (Anti-E) with a gel titer of 1:8 during her second gestation. During her current pregnancy her Anti-E Ab gel titer was 1:32 and an Anti-c Antibody (Anti-c) was also detected. R1R1 panel was used to detect further antibodies since the patient was Anti-E and Anti-c. The initial gel panel could not rule out Duffy Antibody (FyA) and Kidd Antibody (JkB). Two R1R1 panels had already been cross matched and both were compatible. A second gel panel showed Kell antigen (KpA), FyA and JkB, all with a +2 positivity in a R1R1 cell panel (Cell X). Antigen typing labelled the patient as JkB+ and FyA-. One compatible unit was FyB- making FyA- unlikely. One of the cross matched compatible units was FyA+. An additional homozygous R1R1 cell was negative for FyA. Therefore FyA- was ruled out. The positivity on Cell X was then thought to be KpA. A solid phase panel (Cell Y) was conducted and was positive, supporting KpA as the causative factor. A decision was made to repeat our test using the initial patient sample plus a CBC tube. This demonstrated KpA negativity, negating KpA as the causative factor. However the Cell Y positivity in the solid phase panel was still questionable. DiA, a low frequency antibody is also found on this cell. This led to further testing. Another R1R1 cell showed +3 positivity for DiA. Antibody identification confirmed this as DiA with a titer of 2. The patient underwent induction of labor and delivered a healthy neonate. Results (if a Case Study enter NA) N/A Conclusion Since DiA is located in the same panel as KpA, the positive result was presumed to be secondary to KpA. However repeat testing demonstrated KpA negativity and thereby unmasked DiA as the culprit.