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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: 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.

Objective: Lower changes in optical density (450 nm) measurements have been reported in fetuses with anti-Kell anemia compared with those anti-D anemia. The purpose of this investigation was to determine if hemolysis and erythropoiesis differ between anti-Kell and anti-D hemolytic disease., Study Design: Ninety-three pregnancies complicated by either anti-D or anti-Kell alloimmunization were evaluated. Fetal blood samples obtained at the first cordocentesis were tested for the red blood cell antigen type, hemoglobin, hematocrit, reticulocyte count, nucleated red blood cells, total serum bilirubin concentration, umbilical venous respiratory blood gases, serum erythropoietin level, and strength of the direct Coombs test. To determine the evolution of hemolytic anemia in the two antigen groups, these laboratory parameters were repeated on the fetal blood samples triggering the decision to perform a fetal intravascular transfusion (hematocrit <30%)., Results: A total of 65 of 93 fetuses were antigen positive (11 for Kell and 54 for RhD). The mean gestational age and laboratory measurements of antigen- positive, nonanemic fetuses at first blood sampling did not differ significantly between groups. There was a strong inverse relationship observed between the hemoglobin concentration and reticulocyte count independent of gestational age in the anti-D group but not in the anti-Kell group. Eight (73%) fetuses with anti-Kell antibodies and 37 (69%) with anti-D antibodies underwent intravascular transfusion. At the cordocentesis when the decision for transfusion was made, anti-Kell anemic fetuses had lower reticulocyte counts and total bilirubin concentrations. The strong inverse relationship between the hemoglobin and reticulocyte count was again seen only in the anti-D group. In both groups, fetal erythropoietin increased significantly between the first and last blood samplings and in each group were negatively correlated with hemoglobin independent of gestational age., Conclusion: Anti-Kell anemic fetuses have lower reticulocyte counts and total serum bilirubin levels than do comparable anti-D anemic fetuses. This finding argues in favor of fetal blood sampling rather than amniotic fluid analyses for the management of fetal hemolytic disease resulting from Kell antibodies. Unlike RhD alloimmunized fetuses, these fetuses do not manifest an inverse relationship between hemoglobin concentration and reticulocyte count. We speculate that compared to anti-D fetal anemia, anti-Kell anemia is associated with increased hemolysis of nonhemoglobinized or incompletely hemoglobinized erythroid precursors.

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.

Determination of fetal red blood cell Kell antigen is possible on fetal red blood cells obtained at 10 weeks of gestation by chorionic biopsy and may contribute to the management of severe Kell-hemolytic disease.

Maternal anti-Kell antibody was found in 127 of 127,076 pregnancies during a 16-year period (0.1%). Thirteen Kell-sensitized pregnancies ended with a Kell-positive newborn infant, five of these had a poor perinatal outcome (hydrops, intrauterine or neonatal death, hemoglobin less than 7.9 gm, congestive heart failure). Mothers with Kell-positive infants and poor outcome had anti-Kell titers greater than or equal to 1:128 at delivery. With a maternal anti-Kell titer less than 1:32 at delivery, only one baby was Kell positive and mildly affected by hemolytic disease. Spectrophotometric analysis of amniotic fluid (delta optical density at 450 nm) in three of four pregnancies with poor perinatal outcomes revealed values of delta optical density at 450 nm in the high midzone of Liley within 1 week of delivery. Therefore, Kell-sensitized patients have to be managed differently from patients with rhesus sensitization. A management scheme to optimize perinatal outcome in Kell-sensitized pregnancy is described on the basis of this largest reported series of Kell-sensitized pregnancies.