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Hemolytic disease of the fetus and newborn (HDFN) due to an antibody in the Kell blood group system can be associated with severe fetal anemia. This case report details the challenges of managing a Kell null mother with anti-Ku that affected her fetus/newborn. A gravida 4 para 3 woman at term underwent an emergency lower caesarean section because of fetal distress. The baby was intubated because of low oxygen saturation. An urgent request for a hematology workup showed severe anemia and erythroblastosis fetalis. Unfortunately, no compatible blood was found, and the baby died. The case was referred to the National Blood Centre, and anti-Ku was confirmed in a sample sent from the mother. When she presented with her fifth pregnancy, meticulous planning was used to manage this pregnancy. Her family screening revealed one brother with a matching phenotype. Three blood donations were planned for the brother-for freezing, for intrauterine transfusion, and for standby during delivery. Serial anti-Ku titrations of maternal samples were performed, and the fetus was monitored for anemia through middle cerebral artery Doppler scans. Although the anti-Ku titers reached as high as 1024, fetal anemia was never diagnosed. The neonate was delivered safely but was diagnosed with severe pathologic jaundice and anemia secondary to HDFN and congenital pneumonia. The baby was transfused with K 0 packed red blood cells and later discharged to home., (© 2024 Siti A. Wan Mohd Hasni et al., published by Sciendo.)

Objective: To systematically review and meta-analyze alloimmunization among recipients of red blood cells (RBCs) matched for ABO blood type and Rhesus D (ABO+D) antigen compared with those also matched for c, E, and Kell (cEK)., Data Sources: Four online databases (Medline, Scopus, EMBASE, ClinicalTrials.gov ) were searched from March 28, 2023, to April 1, 2024. The search protocol was peer reviewed and published on PROSPERO ( CRD42023411620 )., Methods of Study Selection: Studies reporting alloimmunization as the primary outcome among recipients of RBCs matched for ABO+D or additional cEK matching were included. Patients transfused with unmatched RBCs or a mixture of matching regimens were excluded. Risk of bias was assessed with Cochrane Tool to Assess Risk of Bias in Cohort Studies and Tool for Risk of Bias. Random-effects meta-analysis was used to combine effect estimates., Tabulation, Integration, and Results: Ten studies met criteria. Risk of bias was low. Overall, 91,221 patients were transfused, of whom 40,220 (44.1%) received additional cEK-matched RBCs. The overall rate of alloimmunization was 6.2% (95% CI, 2.5-14.9%) for ABO+D-only matching and 1.9% (95% CI, 0.7-5.1%) when cEK was added. Time of follow-up antibody testing ranged from 6 to 18 months after transfusion. Additional cEK match was associated with significantly less alloimmunization compared with standard ABO+D match (odds ratio [OR] 0.37, 95% CI, 0.20-0.69). This association remained when chronically transfused patients were excluded (OR 0.65, 95% CI, 0.54-0.79) and for alloimmunization to c, E, or K antigens only (OR 0.29, 95% CI, 0.18-0.47)., Conclusion: Additional cEK RBC matching protocols were associated with lower odds of recipient alloimmunization. Given severe sequelae of alloimmunization in pregnancy, routine cEK matching for transfusion in people with pregnancy potential younger than age 50 years in the United States merits consideration., Systematic Review Registration: PROSPERO, CRD42023411620 ., Competing Interests: Financial Disclosure Andra H. James has received honoraria from the Cerus Corp. Jerome J. Federspiel has received honoraria from Hemosquid, SA. The other authors did not report any potential conflicts of interest., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Maternal alloantibodies directed against fetal red blood cell (RBC) antigens may cause potentially life-threatening haemolytic disease of the fetus and newborn (HDFN). Dutch transfusion guidelines therefore prescribe preventive cEK matching for all (pre-)fertile females. To quantify the impact of cEK matching, we compared overall and antigen-specific cumulative RBC alloimmunisation incidences in females and males aged <45 years. Among a multicentre cohort comprised of patients who received their first and subsequent RBC unit between 2005 and 2019, first-formed RBC alloantibodies were detected in 47 of 2998 (1·6%) females and 49 of 2507 (2·0%) males. Comparing females and males, overall alloimmunisation incidences were comparable (3·1% [95% confidence interval (CI) 2·1-4·4] versus 3·5% (95% CI 2·4-4·9, P = 0·853) after 10 units transfused). However, cEK alloimmunisation incidences were significantly lower among females (0·6% (95% CI 0·3-1.5) versus 2·2% (95% CI 1·5-3·4, P = 0·001) after 10 units transfused). Yet, despite cEK-matching guidelines being in effect, 6·5%, 3·6% and 0·2% of all RBC units remained mismatched for c, E or K antigens respectively. Most of these mismatches were almost always due to emergency settings. Even though cEK alloimmunisation was not prevented completely, implementation of cEK matching resulted in an alloantigen-exposure risk reduction of up to 98%., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: During pregnancy, maternal red blood cell (RBC) antibodies can lead to life-threatening fetal hemolysis and anemia. Women can become immunized by a pregnancy or an unmatched transfusion. Our aim was to quantify the effect of a nationwide K-matched transfusion policy for women of childbearing age potential to prevent K-immunization in pregnancy., Study Design and Methods: In this nation-wide policy change evaluation study we determined the occurrence of RBC antibodies before and after introduction of a K-matched transfusion policy and evaluated the cause K alloimmunization 10 years after introduction of this measure. K-matched transfusion for females under 45 years of age is advised in the Dutch transfusion guideline since 2004. We used laboratory data from pregnancies with RBC antibodies identified in the period 1999-2018 obtained as part of a population-based screening program in the Netherlands., Results: Tests of 36 286 pregnancies produced a positive antibody screening result which concerned anti-K in 1550 pregnancies. The occurrence of anti-K decreased from 67.9 to 20.2 per 100 000 pregnancies. The relative risk reduction was 0.70 which largely exceeded the relative risk reduction of 0.27 for antibodies against RBC antigens for which no preventive matching is required. The number of pregnancies at risk for anti-K-mediated disease decreased from 9.7 to 4.2 per 100 000 pregnancies., Conclusions: A K-matched transfusion policy is associated with a major decrease in a number of pregnant women with anti-K and pregnancies at risk for anti-K-mediated disease. A relatively simple measure is now shown to impact prevention of hemolytic disease in the fetus and newborn., (© 2021 The Authors. Transfusion published by Wiley Periodicals LLC. on behalf of AABB.)

Maternal alloantibody-mediated hemolytic disease of the fetus and newborn (HDFN) ranges from no or mild symptoms to severe hydrops and intrauterine fetal demise. Hemolytic anti-D-mediated HDFN proceeds via a long-known mechanism, to which three other pathways to fetal/neonatal anemia may be added: (0) Fetal erythrocyte destruction can proceed by extravascular phagocytosis. (1) An apoptotic pathway has been described for anti-Kell, and anti-Ge3. (2) Erythropoietic suppression may arise from altered or deformed erythroblast architecture in anti-M-mediated disease. (3) Clonal escape from erythropoietic suppression is hypothesized to arise from maternal anti-Jr a immune pressure, albeit this requires further elucidation. Alloantibody-mediated anemic disease of the fetus and newborn (ADFN) is a designation we favor for cases when hemolysis or hyperbilirubinemia are not the dominant features, such as those provoked by anti-Kell, anti-Ge3, anti-M, and anti-Jr a ., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

High-titer antibodies are a cause of false-negative reactions in red blood cell antigen phenotyping, an event referred to as blocked antigen phenomenon (BAP). In hemolytic disease of the fetus and newborn, BAP complicates laboratory workups as fetal phenotype is helpful in confirming the responsible antibody. Acid elution techniques, techniques using ethylenediaminetetraacetic glycine acid, as well as those using chloroquine diphosphate have been used to resolve BAP; however, ethylenediaminetetraacetic glycine acid destroys K-antigen expression and chloroquine diphosphate is not always effective. We report a case of severe hemolytic disease of the fetus and newborn from anti-K where a modified gentle heat elution resolved BAP. Although infrequently considered with isolated reports in the literature, heat elution is simple, is effective, and involves readily available materials in most blood banks., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: There is controversy on critical cut-off values of laboratory testing to select pregnancies at increased risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. Without early detection and treatment, anti-Kell-mediated hemolytic disease of the fetus and newborn may result in progressive fetal anemia, fetal hydrops, asphyxia, and perinatal death., Objective: We aimed to determine the value of repeated anti-Kell titer determination and biological activity measurement using the antibody-dependent cellular cytotoxicity test determination in the management of pregnancies at risk for anti-Kell-mediated hemolytic disease of the fetus and newborn., Study Design: This was a retrospective cohort study of pregnancies with anti-Kell and a Kell-positive fetus, identified from January 1999 through April 2015. Laboratory test results and clinical outcome were collected from the Dutch nationwide screening program and the national reference center for fetal therapy in The Netherlands, the Leiden University Medical Center. Diagnostic accuracy was measured (receiver operating characteristic curves, sensitivity, specificity, positive and negative predictive values) for anti-Kell titers and antibody-dependent cellular cytotoxicity test. The relationship between the titer and antibody-dependent cellular cytotoxicity measurements and the 2 foregoing measurements were computed with a Pearson product-moment correlation coefficient., Results: In a 16-year unselected cohort, representing screening results of 3.2 million pregnancies resulting in live births in The Netherlands, we identified 1026 Kell-immunized pregnancies. In all, 93 pregnant women had anti-Kell and a Kell-positive child, without other red cell alloantibodies. In all, 49 children (53%) needed intrauterine or postnatal transfusion therapy. The first anti-Kell titer showed already a high diagnostic accuracy with an area under the curve of 91%. The optimal cut-off point for the titer was 4 (sensitivity 100%; 95% confidence interval, 91-100), specificity 27% (95% confidence interval, 15-43), and positive predictive value 60% (49-71%). The antibody-dependent cellular cytotoxicity test was not informative to select high-risk pregnancies. Linear regression showed no significant change during pregnancy, when antibody titer and antibody-dependent cellular cytotoxicity test results were compared with every 2 foregoing measurements (P < .0001)., Conclusion: Early determination of the anti-Kell titer is sufficient to select pregnancies at increased risk for hemolytic disease of the fetus and newborn with need for transfusion therapy. If the Kell status of the fetus is known to be positive, a titer of ≥4 can be used to target intensive clinical monitoring., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to present a new method for fetal Kell genotyping by means of the allelic discrimination of K1 and K2 in real-time polymerase chain reaction (PCR)., Methods: Real-time quantitative polymerase chain reaction incorporating an allele-specific primer was developed for detecting the K allele of KEL., Results: By means of this method, the K1/K2 genotype was able to be determined in all blood samples analyzed. Results using cell-free fetal DNA (cffDNA) from two Kell-negative pregnant women confirmed the Kell-positive genotype of fetuses. The real-time PCR analysis also allowed the determination of the fetal fraction using the quantification of Kell-positive DNA., Conclusion: An efficient and reliable strategy for Kell genotyping is herein presented. The method was optimized on cffDNA to create a non-invasive prenatal test which could be routinely used for the prevention of hemolytic disease of the fetus and the newborn (HDFN)., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The management of pregnant women with anti-Jsb is challenging due to the paucity of antigen-negative blood for fetal and neonatal transfusion., Case Report: A 29-year-old woman with anti-Jsb was referred for assessment of recurrent fetal losses. With the presence of the sister as a historically matched donor, she was planned for active surveillance for fetal anemia during pregnancy., Study Design and Methods: The fetus remained well until 21 weeks of gestation when signs of fetal anemia and early hydrops fetalis were noted. Anti-Jsb titer was at 128. The sister's red blood cells (RBCs) were cross-match incompatible. Urgent intrauterine transfusion (IUT) was performed with washed irradiated maternal RBCs, donated after cessation of heparin. The mother was given intravenous iron (IV-Fe) and continued on weekly recombinant human erythropoietin (rHu-EPO)., Results: Repeated IUTs were needed every 1 to 3 weeks. Throughout a 7-week period, three maternal donations were performed with total donated whole blood volume of 1250 mL, supporting four IUTs. At 29 weeks of gestation, the procedure was complicated by umbilical cord hematoma necessitating urgent cesarean section. A male newborn was delivered, transfused at birth, and subsequently treated with phototherapy and five top-up transfusions., Conclusion: This case represents a successful example of managing hemolytic disease of the fetus due to a rare antibody using maternal blood. It also supports previous data on safety of maternal donations during pregnancy and the use of combination of rHu-EPO and IV-Fe as a supportive measure., (© 2013 American Association of Blood Banks.)

Background: Antibodies to Kell antigens can be clinically important but only limited data are published regarding anti-Ku. Missense nucleotide changes in KEL account for the numerous Kell antigens, the K(mod) phenotype, and even the K(null) phenotype., Study Design and Methods: DNA and RNA were extracted from white blood cells and polymerase chain reaction-based assays, cloning, and sequencing were done using standard protocols., Results: The anti-Ku in Proband 1, which caused hemolytic disease and anemia of the fetus and newborn, was a mixture of immunoglobulin (Ig)G1 and IgG2 and gave macrophage indexes ranging from 47.8 to 59.3 (>20 is clinically significant) in a monocyte monolayer assay. The proband, her daughter, and compatible sister had a heterozygous deletion of a G in Exon 18 (Nucleotide c.1972&#95;1975delG) in a KEL*02 allele causing a frameshift. The mechanism for silencing of the other KE*02 allele was undetermined. Proband 2 was heterozygous for a nonsense change (KEL*382C/T; Arg128Stop), a missense change (KEL*244T/C; Cys82Arg), and KEL*578T/C (KEL*01/KEL*02). Direct sequencing of cDNA and cloning showed that the KEL*01 allele had 244C, 382C, 578T and the KEL*02 allele carried 244T, 382T, 578C., Conclusions: We report a novel single-nucleotide deletion, a novel nonsense allele, and a novel missense allele all resulting in the K(null) phenotype. The anti-Ku from Proband 1 was clinically important., (© 2013 American Association of Blood Banks.)

Objective: To determine the clinical spectrum of hemolytic disease due to irregular blood subgroup incompatibility in hospitalized neonates., Study Design: The medical records of the all hospitalized newborn patients diagnosed with indirect hyperbilirubinemia due to subgroup incompatibility in Kell, C, c, E, and e systems were included in the study. Data from 106 newborns with hemolytic jaundice due to irregular blood subgroups were retrospectively evaluated, and clinical and laboratory findings were compared between patients . The treatment modalities given to the patients of each subgroup types and the laboratory findings and treatment modalities of the cases according to Coombs tests results were also analyzed. Fetal affection of the hemolysis and also fetal losses due to irregular red-cell alloimmunization were not detected in prenatal course, as there was no follow-up of these pregnancies., Results: The mean postnatal hospitalizing age was 6.1 ± 5.2 days after birth. The mean total bilirubin level and the mean hemoglobin value on hospitalization were 343.7 ± 63.3 µmol/L (=20.1 ± 3.7 mg/dL) and 14.9 ± 3.4 g/dL, respectively. Of 106 patients identified with irregular subgroup incompatibility, 40 infants (37.7%) were associated with C, 22 (20.8%) with c, 30 (28.3%) with E, 9 (8.5%) with e, and 5 (4.7%) with Kell subgroup system. Positive Coombs tests (either direct and/or indirect) occurred in 28.3% of the study cases. Hydrops fetalis was determined in 5 of 106 neonates (4.7%). Twenty-two of 106 (20.8%) patients required total exchange transfusion. Positive Coombs test in cases required total exchange transfusion was 63.6%., Conclusion: Our data expose the magnitude and spectrum of the potential developing severe hemolytic disease and immune hydrops due to irregular subgroup incompatibility. Minor group antibody screening is recommended both in the mother and the high-risk infants with hyperbilirubinemia and hemolytic disease of the newborn., (Copyright © 2012 Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.)

Objective: To evaluate neonatal outcome in Kell haemolytic disease compared to Rh D haemolytic disease., Study Design: Retrospective study of all (near)-term neonates with Kell (n=34) and Rh D haemolytic disease (n=157) admitted to our centre between January 2000 and December 2008. We recorded the need for exchange transfusion and top-up transfusions up to 3 months of age., Results: Neonates in the Kell group required less days of phototherapy than neonates in the Rh D group [2.4 vs. 4.1 days, respectively (P<0.01)]. The percentage of neonates requiring an exchange transfusion was lower in the Kell group than in the Rh D group [6% (2/34) and 62% (98/157), respectively (P<0.01)]. The percentage of neonates in the Kell group and Rh D group requiring a top-up transfusion was 62% (21/34) and 72% (113/157), respectively (P=0.20). The median number of top-up transfusions per neonate in the Kell group and Rh D group was 1 [interquartile range (IQR) 0-2] and 2(IQR 0-2), respectively (P=0.07)., Conclusion: Neonates with Kell haemolytic disease require less phototherapy and less exchange transfusions compared to neonates with Rh D haemolytic disease, but an equal number of top-up transfusions., (© 2010 The Author(s). Vox Sanguinis © 2010 International Society of Blood Transfusion.)

Antibodies to antigens in the Kell blood group system are usually immunoglobulin G, and, notoriously, anti-K, anti-k, and anti-Kp(a) can cause severe hemolytic transfusion reactions, as well as severe hemolytic disease of the fetus and newborn (HDFN). It has been shown that the titer of anti-K does not correlate with the severity of HDFN because, in addition to immune destruction of red blood cells (RBCs), anti-K causes suppression of erythropoiesis in the fetus, which can result in severe anemia. We report a case involving anti-Kp(a) in which one twin was anemic and the other was not. Standard hemagglutination and polymerase chain reaction (PCR)-based tests were used. At delivery, anti-Kp(a) was identified in serum from the mother and twin A, and in the eluate prepared from the baby’s RBCs. PCR-based assays showed twin A (boy) was KEL*841T/C (KEL*03/KEL*04), which is predicted to encode Kp(a+b+). Twin B (girl) was KEL*841C/C (KEL*04/KEL*04), which is predicted to encode Kp(a–b+). We describe the first reported case of probable suppression of erythropoiesis attributable to anti-Kp(a). One twin born to a woman whose serum contained anti-Kp(a) experienced HDFN while the other did not. Based on DNA analysis, the predicted blood type of the affected twin was Kp(a+b+) and that of the unaffected twin was Kp(a–b+). The laboratory findings and clinical course of the affected twin were consistent with suppression of erythropoiesis in addition to immune RBC destruction.

Introduction: The frequency of occurrence of RhD alloimmunization, due to preventive protocols, is decreased in our country, but more often there are other antigens that emerge as a cause of hemolytic disease of fetus. The most prominent is Kell antigen, which promotes specific course of disease based on an innate pathogenetic mechanism. Anti-Kell antibody production is, just as in other atypical antibodies, provoked with transfusion of incompatible blood. Except for the immune-mediated hemolysis, anti-Kell antibodies can also inhibit the function of progenitor (erytroid and megakariocyte) cell lines., Case Report: We present the case of G1P1 woman in whom a distinct fetal hydrops was sonographically detected in the 28th week of pregnancy. The results of immunological tests undoubtedly pointed to Kell immunization (anti-Kell antibody titer was more than 1:32), and antenatal tests for evaluation of fetal condition (Doppler ultrasound and CTG) clearly showed the severe form of hemolytic disease. We concluded that the fetus was in a hopeless, terminal stage of the disease, and then decided to terminate the pregnancy., Conclusion: The only clinical approach to a problem of Kell alloimunization is active one. Early cordocentesis is recommended as the optimal method for evaluation of fetal condition. The clinical outcome of the fetus will strictly depend on a timely intrauterine transfusion (IUT) procedure. Prophylaxis emerges as a crucial factor in prevention of Kell-alloimmunization. It is to be considered that all females in childhood and throughout the reproductive period should take only K1-negative blood transfusion in order to decrease the incidence of Kell-alloimmunization.

Aim: 1) We have presented our experiment conducted to detect anti-K antibodies from the Kell-system in pregnant women and their connection with potential destruction of foetal red cells, which may result in haemolytic disease of the foetus and the newborn (HDFN). 2) We have also indicated serological and molecular methods important for a proper diagnosis., Material and Methods: 27 women with anti-K. Serological diagnosis of K antigen in fathers and children. KEL1 gene examination in foetuses from DNA isolated from foetal cells contained in amniotic fluid, using discrimination of alleles--real-time PCR method., Results: Anti-K were detected in most women after blood transfusion, the fathers were usually K negative. Foetomaternal incompatibility was found in 6 out of 27 women. Haemolytic disease was observed in 5 cases: 3-severe, 1-fatal, 1-mild. Foetal genotyping allowed us to avoid cordocentesis in two pregnant women, it appeared that both foetuses have not received KEL1 gene from heterozygous (Kk) fathers--in the previous pregnancies the children had died because of HDFN., Conclusions: 1) In every pregnant woman with anti-K, the K antigen should be examined in the father. 2) In every K+ father the phenotype should be evaluated and if he is heterozygote (Kk), the fetal KEL1 gene must be examined, to avoid unnecessary cordocentesis. 3) If KEL1 gene is not detected in the foetus, HDFN will not occur. 4/Foetal KEL1 genotyping may be performed in all mothers with anti-K and heterozygous father in our Department, after providing the material from the amniocethesis.

Background: Hemolytic disease of the fetus and newborn (HDFN) is a severe disease, resulting from maternal red cell (RBC) alloantibodies directed against fetal RBCs. The effect of a first-trimester antibody screening program on the timely detection of HDFN caused by antibodies other than anti-D was evaluated., Study Design and Methods: Nationwide, all women (1,002 in 305,000 consecutive pregnancies during 18 months) with alloantibodies other than anti-D, detected by a first-trimester antibody screen, were included in a prospective index-cohort study. In a parallel-coverage validation study, patients with HDFN caused by antibodies other than anti-D, that were missed by the screening program, were retrospectively identified., Results: The prevalence of positive antibody screens at first-trimester screening was 1,232 in 100,000; the prevalence of alloantibodies other than anti-D was 328 in 100,000, of which 191 of 100,000 implied a risk for occurrence of HDFN because the father carried the antigen. Overall, severe HDFN, requiring intrauterine or postnatal (exchange) transfusions, occurred in 3.7 percent of fetuses at risk: for anti-K in 11.6 percent; anti-c in 8.5 percent; anti-E in 1.1 percent; Rh antibodies other than anti-c, anti-D, or anti-E in 3.8 percent; and for antibodies other than Rh antibodies or anti-K, in none of the fetuses at risk. All affected children, where antibodies were detected, were promptly treated and healthy at the age of 1 year. The coverage validation study showed a sensitivity of the screening program of 75 percent. Five of 8 missed cases were caused by anti-c, with delay-induced permanent damage in at least 1., Conclusion: First-trimester screening enables timely treatment of HDFN caused by antibodies other than anti-D, however, with a sensitivity of only 75 percent. A second screening at Week 30 of c- women will enhance the screening program. Severe HDFN, caused by antibodies other than anti-D, is associated with anti-K, anti-c, and to a lesser extent with other Rh-alloantibodies.

Objectives: Few reports have been published of the current clinical management of anti-Kell alloimmunization in pregnancy; its low frequency of occurrence means that the few long series published have covered very ample time periods in which different kinds of clinical management have overlapped. The objective of the present paper is to present our experience in the current clinical management of pregnant women who are positive for the anti-Kell antibody., Study Design: A retrospective analysis was carried out of the case histories of pregnant women who were alloimmunized for the Kell antigen and who were studied and/or treated at the Department of Fetal Medicine in the Virgen de las Nieves University Hospital in Granada (Spain), between 2000 and 2004. The clinical management included the basal measurement of the titre of antibodies, the identification of the paternal phenotype (and that of the fetus, if necessary), the ultrasonographic monitoring of the fetus to detect signs of anaemia, sampling of fetal blood by cordocentesis when fetal anaemia was suspected, and fetal intravascular transfusion when necessary., Results: Of the 10 pregnancies with anti-Kell antibodies, The Kell antigen was confirmed in the fetus in three cases, in all of which moderate to severe fetal anaemia developed, requiring fetal intravascular transfusions. Although one of the fetus developed antenatal hydrops, a good perinatal result was advised., Conclusions: The current approach to anti-Kell alloimmunization enables pregnant women who have Kell-positive fetuses to be treated successfully.

Objective: To evaluate the usefulness of the obstetric history and the maternal serum Kell antibody titer in the management of pregnancies with Kell alloimmunization., Methods: In a retrospective cohort study of 41 pregnancies complicated by Kell alloimmunization, the obstetric history, divided into presence or absence of a previous Kell-positive child, and Kell antibody titers in the index pregnancy were correlated with the gestational age at the onset of fetal anemia., Results: Women with a previous Kell-positive child had a lower gestational age at the first intrauterine transfusion compared with those without a previous Kell-positive child (P=.01). However, in two of 29 pregnancies in the latter group, severe fetal anemia requiring transfusion was detected before 20 weeks of gestation. In neither group were maternal Kell antibody titers significantly correlated with gestational age at first intrauterine transfusion (P=.62 and P=.72, respectively). In all but two pregnancies (1:2 and 1:4, respectively), antibody titers were at least 1:32 before the first intrauterine transfusion., Conclusion: For timely detection of all cases of severe fetal anemia, Kell-alloimmunized pregnancies with a Kell-positive fetus and titers greater than or equal to 1:2 should be closely monitored from 16 to 17 weeks of gestation onward.

Objective: Intrauterine transfusion (IUT) is a life-saving therapy for the severely anemic fetus with hemolytic disease. However, maternal additional antibody formation is a complication of the procedure. In this study, we determined antibody formation after introduction of preventive Rh-D, -C, -c, -E, and -e and K matching of IUT donors., Study Design: This was a retrospective follow-up study., Results: During an 11-year period, 686 Rhesus- and K-matched IUTs were performed in 233 pregnancies and in 95% (652/686) posttransfusion antibody testing was performed after a median interval of 21 days. Twenty-five percent (53/212) of the women formed 64 new antibodies and, compared to our previous study, this incidence was not decreased by the use of Rhesus- and K-matched donors. After delivery, 72% (153/212) of the women had multiple RBC antibodies. Additional antibodies were in 48% (31/64) directed against Rhesus and K antigens, induced by the fetus, or as natural antibodies. In 52% (33/64) the antibodies were directed against non-Rhesus and -K antigens and in 65% (11/17) of eligible cases the IUT donor and not the fetus expressed the corresponding antigen(s)., Conclusion: Despite Rhesus- and K-matching, women treated with IUTs still show strikingly broad red cell alloimmunization. More extensive IUT donor red cell matching, including FY, JK, and S antigens, to reduce the formation of new red cell antibodies should be explored.

Background: The management of a pregnant woman with the rare Ko phenotype and anti-Ku is a special challenge, because matched blood is extremely rare and the possibility of severe hemolytic disease of the newborn is high., Case Report: A 30-year-old woman with rare Ko (Knull) phenotype presented at 18 weeks of gestation with positive indirect agglutination test results. She had anti-Ku due to previous blood transfusion, one pregnancy, and two abortions., Study Design and Methods: During this pregnancy, anti-Ku titers ranged from 1024 to 4096. At the 26th week of gestation ultrasound showed a hydropic fetus and urgent intrauterine exchange transfusion was performed with the maternal red blood cells (RBCs). Recombinant human erythropoietin (rHu-EPO) and intravenous (IV) iron were administered to the mother to ensure an adequate supply of matched RBCs for intrauterine transfusions and possible perinatal hemorrhage., Results: Intrauterine transfusions were repeated every 1 to 3 weeks. By 35 weeks 2 days of gestation, the mother had donated 4 units of blood, and four intrauterine transfusions had been performed. Cesarean section was then decided and a healthy male newborn was born. He was treated with phototherapy but without exchange transfusions. By the 15th day of life rHu-EPO was administrated to the newborn because of anemia. The maternal RBCs completely disappeared from the child's blood by Day 100., Conclusions: As shown in this case, treatment with rHu-EPO and IV Fe has effectively increased the mother's capacity to donate RBCs for autologous use and intrauterine transfusions, with no adverse effects to the mother or the child.

Anti-k is a Kell-related antibody. There is little correlation between the maternal antibody titre and the severity of haemolytic disease of the foetus and newborn, and anaemia is usually associated with low bilirubin levels. Severe erythroblastosis has been reported with a low titre anti-k (IAT 8-16). We report a case of severe haemolytic disease of the newborn (HDN) due to anti-k. HDN was associated with a normal bilirubin level and reticulocytopenia. The foetus was monitored by ultrasound, and delivery by elective caesarean section (CS) was planned. The mother was admitted 1 week before the expected date of delivery, and the infant was delivered by urgent CS. The infant required exchange transfusion. As suitable plasma-reduced (k antigen(-)) red cell units were not readily available, k- SAGM red cell units (preserved in extended storage media: SAGM sodium chloride, adenine, glucose and mannitol) were provided. The post-transfusion Hb remained stable, and the infant did not require further transfusion support. Our findings (reticulocytopenia and normal bilirubin levels) support the hypothesis that the pathogenesis of anaemia and haemolysis in anti-k HDN may be similar to that in anti-K (suppression of erythropoesis and immune destruction of K+ erythroid progenitor cells by macrophages in the foetal liver). The ideal product for exchange transfusion is plasma-reduced RBC, less than 5-days old. We provided a 4-day-old SAGM red cell unit for exchange transfusion in a term infant, and this was uneventful. Caution should be taken, however, and renal function and electrolyte levels should be monitored closely. More information is required regarding the safety of SAGM units for exchange transfusion.

Introduction: Kell alloimmunization is a rare disease, although its incidence is the highest after after anti-D alloimmunization., Methods: We report two recent cases and a review of the literature to describe practical management of Kell alloimmunization in pregnancy., Discussion: When an immunization against the Kell antigen was diagnosed, amniocentesis was performed at 14 weeks gestation to determine the fetal blood group. If the fetus was Kell positive, a first fetal blood sample was drawn at 17 weeks gestation in case of fetal hydrops, and at 20 weeks without fetal hydrops. The diagnosis of anemia led to in utero transfusion. A second fetal blood sample was taken at 8 to 10 days, every two weeks during the second trimester and every three or four weeks during the third trimester. Fetal well-being was assessed with weekly sonography and rates of hemoglobin decline. These measures enable adapting the frequency of fetal blood sampling.

A grave form of HDN (haemolytic disease of the new-born) is described in female twins, caused by Kell, E and Vel isoimmunisation. The weakly vital and anaemic new-born babies were hospitalised with signs of respiratory distress on the first day of their life after the delivery by Caesarean section in the 38 (th) week of pregnancy in the General Hospital Dubrovnik. Already during the first hours of their life jaundice developed with a high bilirubin level for their age. The direct Coombs' test on the twins and the indirect Coombs' test on the mother were positive. Immuno-haematological analysis proved the presence of anti-Kell, anti-E and the very rare anti-Vel antibodies in the mother's serum and in the plasma of both twins. We had no possibility to obtain appropriate blood for the indicated exsanguine transfusion because cross-probes with the accessible blood samples were positive. Up to the fourteenth day of life the anaemia deepened and was aggravated in one twin, the Kell positive one (phenotype CcDEe,Kk) in relation to the other, the Kell negative (phenotype CcDEe,kk) twin. The recovery of the female twins started on the 15 (th) day of life, after the transfusion of blood (phenotype: 0,ccddee, Vel negative, Kel negative), received from the bank of rare blood groups in London. This is the first described case of haemolytic disease of the new-born caused by antibodies on the antigen Kell, E and Vel. The low frequency of immunisation with rare antigens such as Kell, E and Vel, does not exclude the possibility of the occurrence of grave forms of haemolytic disease. All pregnant women with a positive indirect Coombs' test should be further immuno-haematologically tested in order to identify the antibodies type so that the treatment of the new-borns could be commenced in time.

The authors report on a fatal case of hemolytic disease of the newborn (HDN) due to anti-K antibodies with subsequent trilineage pancytopenia in a preterm infant of 28 weeks gestational age, with pronounced leukopenia and neutropenia. In addition, molecular typing of the Kk polymorphism was necessary to confirm HDN. This case of HDN associated with anti-K provides additional evidence that trilineage pancytopenia due to suppressed hematopoiesis is part of the disease. Therefore, antibodies against antigens of the Kell blood group system should be considered as a potential cause of unexplained inhibition of myelopoiesis.

We assessed the clinical outcome of pregnancies with non-Rh-D antibody in Northern Ireland using retrospective case note review. During the study period (April 1999- March 2000) 186 women with clinically significant antibodies were identified from the records of the antenatal laboratory of the Northern Ireland Blood Transfusion Service. Eighty-five women were included in the study using the criteria mentioned above. None of the fetuses required intrauterine transfusion during this period. One baby required exchange transfusion, three were given top-up transfusions and 17 had phototherapy. Nine babies with a positive direct antiglobulin test (DAT) received no treatment. The incidence of anti-Kell could be reduced by transfusing Kell negative red cells to premenopausal women. It is important that all pregnant women are tested at least twice in their pregnancy to detect the antibodies formed late in the pregnancy. It is useful to formulate a standard protocol for antenatal interventions. Non Rh-D antibodies can cause significant anaemia for up to six weeks in the neonatal period, hence early detection of maternal antibodies is important so that the neonates are followed up for an appropriate length of time.

Recent data suggest that antibody-mediated suppression of erythroid progenitors may contribute to the anti-Kell-induced alloimmune hemolytic disease of the newborn (HDN). A 32-week-old girl who was positive for Kell was born to a mother who was negative for Kell but known to have anti-Kell antibodies. After birth, the baby had HDN and hyperbilirubinemia develop (peak bilirubin 21 mg/dL at day 9 of life). which was treated with phototherapy. Although the hyperbilirubinemia resolved, she became progressively anemic (hematocrit 22%) with an inappropriately low reticulocyte response (1.1%) and erythropoietin (EPO) level (20 mU/mL). To avoid the need for a blood transfusion, she was treated with recombinant erythropoietin (rEPO) and oral iron supplements. One week after starting EPO, the reticulocyte count increased to 9.1%. Erythropoietin therapy was continued for a total of 9 weeks, with resolution of her anemia at the end of therapy (hematocrit 35%). Thus, we were able to successfully treat the anemia with rEPO with avoidance of blood transfusion. This patient demonstrates that the antibody-mediated erythroid suppression in Kell alloimmune anemia can be overcome by rEPO. Recombinant erythropoietin should therefore be considered in the management of infants with severe or hypoproliferative anti-Kell-associated anemia.

A case of anti-Js(b) in pregnancy was associated with unexpectedly severe haemolytic disease of the newborn, requiring urgent exchange transfusion. Clinical signs of fetal distress were evident at 35 weeks of gestation in a sixth pregnancy. A Js(b+) baby from a previous pregnancy had been unaffected. This case report illustrates the difficulties of predicting severity on the basis of anti-Js(b) titre, and highlights issues relating to the problems of using reconstituted frozen red cells from the rare red cell bank for exchange transfusion.

Objective: Review the fetal/neonatal outcome and management of pregnancies associated with alloimmunization to irregular anti-red-cell antibodies., Study Design: Computerized MEDLINE search using keywords that included hemolytic disease of the newborn (HDN) and the specific family of anti-red-cell antibody, such as anti-Kell antibody., Results: A review of the prevalence of antibodies associated with HDN in reproductive age women revealed a marked decrease in the incidence of anti-RhD. An increasing incidence of anti-K1 antibody has been noted in the US, a trend not seen in other countries. Guidelines for intervention in cases of irregular antibodies are limited by the bias of anecdotal reports in the literature in favor of severe cases of HDN., Conclusions: In cases of Kell, M, Duffy and Kidd alloimmunization, DNA techniques using amniotic fluid can be used to exclude antigen-negative fetuses. Kell (K1 and K2) alloimmunization should be managed somewhat differently from RhD due to the unique ability of these antibodies to suppress the fetal erythropoietic response.

During pregnancy irregular blood group antibodies, originating either from earlier pregnancies or from blood transfusions, may severely jeopardize both mother and child. Three patients are described with pregnancy-associated blood group incompatibility. In one case of Kell antagonism a previous child had reportedly died of cot death, but in retrospect it had most probably suffered from erythroblastosis fetalis as a result of anti Kell antibodies. In the second case, a twin pregnancy, the diagnosis of neonatal haemolytic anaemia on the basis of blood group incompatibility with a very rare antibody (anti-Kpb) had been established in the previous child. No precautions had been taken during this pregnancy, putting both mother and children at risk. All three children recovered, the twins after repeated transfusion of Kpb-free erythrocytes. The described cases emphasize the importance of being informed about the presence of antibodies during pregnancy. Such information can only be obtained by assessing the antibody status during pregnancy. In the Netherlands, the screening of all pregnant women for the presence of irregular antibodies was introduced last year.

Objective: To inventory prevalence and morbidity of haemolytic disease of newborn caused by irregular anti-erythrocyte antibodies other than antirhesus-D., Design: Prospective registration study., Method: All paediatricians (n = 380) in general hospitals and contact persons (n = 79) in university hospitals were asked for monthly reports of clinical cases of haemolytic disease of newborn during 2 years (1996-1997)., Results: Response was 97%. A total of 130 reports were received in two study years, 49 of which could not be confirmed as non-RhD-non-AB0 antagonism. In the group of which the transfusion history was known (n = 60), 29 pregnant women (48%) had received transfused blood at some time. Of the antibodies found, anti-c, anti-E and anti-K were the most frequent. The direct antiglobulin test was positive in 61 of the 81 cases, negative in 10 cases, while in 10 cases it was unknown or false-negative due to earlier intrauterine transfusions (in three neonates). The highest bilirubin levels recorded were 572, 559 and 520 mumol/l (all three with maternal anti-c antagonism). Therapeutic data were known concerning 80 of the 81 newborn: 21 (16%) received no treatment, 24 (29%) only phototherapy and the others--in addition to phototherapy if any--also blood transfusion, exchange transfusion or intrauterine transfusion, or a combination of these., Conclusion: It was calculated that the actual prevalence of irregular anti-erythrocyte antibodies in Dutch pregnant women probably amounts to approximately 0.25%. This finding may possibly be confirmed since starting 1 July 1998 all pregnant women in the country are screened for the presence of these antibodies. It is recommended that girls and women in the reproductive age group should receive primary prevention of development of irregular anti-erythrocyte antibodies by application of a selective blood transfusion policy, taking into account the occurrence of the antigens c, E and K.

The study was conducted to report on the use of molecular biology methods and pregnancy outcome in women sensitized to either Rhesus D (RhD) or Kell 1 (K1) antigens. Paternal RhD genotype was determined by DNA amplification of an RhD-specific sequence from single sperm cells. Paternal Kell phenotype was determined by serologic assays using peripheral blood samples, and the fetal RhD or Kell-type status were established by the polymerase chain reaction (PCR) with amniotic cells. Thirteen women (14 pregnancies, one with twins) sensitized to RhD and four sensitized to K1 antigens, comprised the study group. All had paternal heterozygosity to either D or K1 antigens. Nine fetuses were RhD positive and five were RhD negative. An additional woman underwent early spontaneous abortion. The nine RhD-positive fetuses underwent a total of 41 invasive procedures. One fetus with hydrops fetalis died in utero after intrauterine blood transfusion. All the remaining RhD-positive fetuses were delivered after 33 weeks gestation, and all those who were RhD negative were delivered at term. Four women were sensitized to the K1 antigen; in three, the fetus was found to be K1 negative, and in one, K1 positive, necessitating intrauterine blood transfusion. In all cases, the results of RhD or K1 genotype analyses from amniotic fluid were compatible with fetal/neonatal red blood cell RhD or Kell phenotypes. In conclusion, the use of molecular biology techniques represents a major advance in the clinical management of RhD and Kell alloimmunization.

Background: In alloimmune anemia of the newborn, the level of hemolysis caused by the presence of antibodies to antigens of the Kell blood-group system is less than that caused by antibodies to the D antigen of the Rh blood-group system, and the numbers of reticulocytes and normoblasts in the baby's circulation are inappropriately low for the degree of anemia. These findings suggest that sensitization to Kell antigens results in suppression of fetal erythropoiesis as well as hemolysis., Methods: We compared the growth in vitro of Kell-positive and Kell-negative hematopoietic progenitor cells from cord blood in the presence of human monoclonal anti-Kell antibodies and anti-D antibodies and serum from women with anti-Kell antibodies., Results: The growth of Kell-positive erythroid progenitor cells (erythroid burst-forming units and colony-forming units) from cord blood was markedly inhibited by monoclonal IgG and IgM anti-Kell antibodies in a dose-dependent fashion (range of concentrations, 0.2 to 20 percent), but monoclonal anti-D antibodies had no effect. The growth of these types of cells from Kell-negative cord blood was not affected by either type of antibody. Neither monoclonal anti-Kell antibodies nor monoclonal anti-D antibodies inhibited the growth of granulocyte or megakaryocyte progenitor cells from cord blood. Serum from 22 women with anti-Kell antibodies inhibited the growth of Kell-positive erythroid burst-forming units and colony-forming units but not of Kell-negative erythroid burst-forming units and colony-forming units (P<0.001 for the difference between groups). The maternal anti-Kell antibodies had no inhibitory effects on granulocyte-macrophage or mega-karyocyte progenitor cells from cord blood., Conclusions: Anti-Kell antibodies specifically inhibit the growth of Kell-positive erythroid burst-forming units and colony-forming units, a finding that supports the hypothesis that these antibodies cause fetal anemia by suppressing erythropoiesis at the progenitor-cell level.

Antenatal genotyping of the fetus is now in widespread use as an aid to the clinical management in cases where there is the potential of haemolytic disease of the newborn occurring. The rapid diagnosis of an antigen-negative fetus will preclude the requirement for further, potentially risky invasive procedures being performed, whilst the determination of an antigen-positive fetus allows the potential of intensifying obstetric care for this pregnancy. Molecular genotyping is a major clinical application which has led from the determination of the molecular bases of blood group antigens expressed, most of which have been defined at the level of the gene. All assays used are dependent on the Polymerase Chain Reaction amplification of fetal DNA derived from either amniotic fluid or chorionic villi. Recent work has explored the potential of utilising fetal cells found to be present in maternal peripheral blood as a source of nucleic acid for prenatal diagnosis. Using non-invasive methods will preclude exposing mother and fetus to the potential hazards of invasive methods (amniocentesis, chorionic villus sampling and cordocentesis) which include miscarriage, fetal malformations and further maternal alloimmunisation.

We describe a case of intrauterine foetal death at 32 weeks gestation with signs of hydrops foetalis without erythroblastosis. The hydrops foetalis appeared to be caused by blood group incompatibility. Irregular antibodies of anti-K specificity were found in the serum of the mother, while the father was positive for the K-antigen. The antibody dependent cell-mediated cytotoxicity (ADCC) test with serum of the mother was positive. This case shows the characteristics of haemolytic disease of the newborn by anti-K. Moreover, it underlines the necessity of both adequate follow-up of individual cases, and screening for irregular antibodies in all pregnancies as well as central registration of screening results.

Anti-Js(b) has not been reported to cause severe hemolytic disease of the newborn requiring intrauterine evaluation and treatment. We now report on such a patient with high-titered anti-Js(b) causing fetal hydrops with demise in one pregnancy, followed by a pregnancy treated with multiple intrauterine fetal transfusions.

Objective: Our purpose was to test the hypothesis that maternal anti-Kell alloimmunization produces fetal anemia by erythroid suppression., Study Design: Erythropoiesis in 11 anemic fetuses from maternal anti-Kell alloimmunization was compared with that in 11 fetuses where the mother was alloimmunized to RhD; each was matched for hematocrit, gestational age, hydrops, and perinatal outcome. Comparisons of the difference were performed by either paired t or Wilcoxon tests., Results: The anti-Kell group had reduced reticulocytosis (p = 0.007) and erythroblastosis (p = 0.045) and lower amniotic fluid bilirubin concentrations (p = 0.02) in comparison with the anti-D group. No correlation was found between hematocrit and reticulocytosis in the anti-Kell group, whereas the anti-D group had a significant linear relationship (r = 0.63, p < 0.05), indicating a progressive reticulocytosis in response to the degree of anemia., Conclusion: These findings suggest that erythroid suppression, rather than hemolysis, is the predominant mechanism in producing fetal anemia related to maternal Kell alloimmunization. Fetal blood sampling is the investigation of choice in the evaluation of anemia related to maternal Kell alloimmunization, because reduced hemolysis means amniotic fluid bilirubin concentrations correlate poorly with anemia.

The first case of hemolytic disease of the newborn (HDN) due to anti-Ula antibodies is described. The infant had severe anemia with a positive direct antiglobulin test with anti-IgG that required blood transfusion. But jaundice was not severe enough for exchange transfusion or phototherapy.

We report a case of clinically significant hemolytic disease of the newborn due to Kpb alloimmunisation requiring obstetric intervention. This case and a review of the literature are in contrast to reviews of hemolytic disease of the newborn that either ascribe no significance to the Kpb antigen or suggest that it causes only rare or mild disease. Analysis of our Kpb-negative donor pool suggests that prior transfusion greatly increases the chance of alloimmunisation. The role of frozen rare donor registry cells as a public resource is emphasised.

The role of high-dose intravenous (IV) gamma globulin in the treatment of erythroblastosis fetalis was assessed in five pregnancies with severe Rh (four) or Kell (one) isoimmunization. These women were treated with IV gamma globulin (1.0 g/kg body weight) once a week. In addition, fetal blood transfusions were performed when indicated. In four patients with Rh sensitization, high-dose IV gamma globulin treatment had no apparent effect on the total number of intrauterine transfusions required, the interval between transfusions, or the volume of blood required at each transfusion. The treatment did not prevent fetal hydrops and had no effect on maternal antibody titers. In one patient with Kell sensitization, however, the course of the disease was less severe than anticipated, suggesting that IV gamma globulin treatment may have modified the severity of the disease. We conclude that high-dose IV gamma globulin does not appear to be useful in the treatment of severe Rh disease. Its role in Kell and other types of red-cell isoimmunization deserves further evaluation.

In a 10-year period, 407 of 350,000 pregnancies showed maternal anti-Kell allo-immunization, i.e., an incidence of 1.16 per 1000 pregnancies. About 88% of Kell immunized women gave a history of previous transfusion. There were 51 pregnancies with Kell positive partners (all Kk) resulting in 10 Kell positive babies, of whom six had a positive direct antiglobulin test (DAGT). There were two stillbirths due to haemolytic disease of the newborn, when the maternal anti-Kell titres were 1/256. One baby was severely anaemic and given a top-up transfusion, and two babies were jaundiced and given phototherapy. A policy for management of Kell sensitized pregnancies is outlined, based upon maternal anti-Kell titre and where appropriate fetal blood sampling.