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Hemolytic Disease of the Fetus and Newborn (HDFN) is a condition that affects 1 to 2 out of 1000 patients during pregnancy (1). When an alloantibody is present, it is essential to identify its nature in order to organize appropriate follow-up. Kell-mediated HDFN is rare; it occurs in about 5% of Kell alloimmunized pregnant women. It is important to note that in case of anti-Kell immunization, the severity of HDFN is not correlated with maternal antibody titers, and anemia tends to occur earlier and more severely. Therefore, early diagnosing and management of this condition is crucial. In the management of severe fetal anemia due to Kell immunization, available treatments include in utero transfusion (IUT), immunoglobulin therapy. Other alternative treatments exist, such as plasmapheresis. Intravenous immunoglobulin (IVIG), a noninvasive therapeutic approach, acts through multiple mechanisms. IVIG has been evaluated in cases of RhD immunization with high maternal antibody titers and a history of pregnancies involving early hydrops or intrauterine death. Regarding the potential benefits of intravenous IgG therapy, it may delay the need for early IUT, reduce the overall reliance on IUT, and have a positive impact on obstetric outcomes. This case of IV IgG therapy of anti-Kell immunization offers a thought-provoking avenue for future exploration., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest in relation to this work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Hemolytic disease of the fetus and newborn (HDFN) is a condition caused by maternal alloantibodies against fetal red blood cells (RBCs) that can cause severe morbidity and mortality in the fetus and newborn. Adequate screening programs allow for timely prevention and intervention resulting in significant reduction of the disease over the last decades. Nevertheless, HDFN still occurs and with current treatment having reached an optimum, focus shifts toward noninvasive therapy options., Areas Covered: This review focusses on the timely identification of high risk cases and antenatal management. Furthermore, we elaborate on future perspectives including improvement of screening, identification of high risk cases and promising treatment options., Expert Opinion: In high-income countries mortality and morbidity rates due to HDFN have drastically been reduced over the last decades, yet worldwide anti-D mediated HDFN still accounts for 160,000 perinatal deaths and 100,000 patients with disabilities every year. Much of these deaths and disabilities could have been avoided with proper identification and prophylaxis. By implementing sustainable prevention, screening, and disease treatment measures in all countries this will systemically reduce unnecessary perinatal deaths. There is a common responsibility to engage in this cause.

Jaundice is one of the most common situations during the neonatal period. Alloimmune haemolytic disease of the fetus and newborn (AHDFN) is a major cause of pathological jaundice during the neonatal period. Since the establishment of anti-D prophylaxis, other antigens have gained greater clinical importance. The maternal antierythrocyte antibody screen is of great importance in monitoring pregnancy and in predicting the risk of AHDFN. A positive result should alert to the possibility of AHDFN and promote close surveillance of fetal anaemia, as well as neonatal anaemia and hyperbilirubinaemia. We describe a case of AHDFN due to incompatibility of the Rhesus c (Rhc) subgroup, diagnosed in pregnancy, but without effective transmission of information in the perinatal period, so a positive maternal antierythrocyte antibody screen was missed. This case highlights the importance of non-RhD antigens in this disease, but also the importance of a successful handoff of information in the delivery room., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To determine the longitudinal trends of middle cerebral artery peak systolic velocity (MCA PSV) in fetuses with mild or moderate hemolytic disease according to the need for postnatal therapy., Design: Prospective cohort study., Setting: University referral center., Sample: Twenty-three fetuses from singleton alloimmunized pregnancies., Methods: Serial measurements of MCA PSV were performed. After delivery, newborns were grouped by the need for postnatal management into mild hemolytic disease, which required no or only phototherapy (n = 14, group 1), and moderate hemolytic disease, where postnatal top-up or exchange transfusions were required (n = 9, group 2)., Main Outcome Measures: Serial Doppler MCA PSV data transformed to multiples of the median, analyzed with linear regression and exponential models., Results: We performed 83 measurements in group 1: 3-8 per fetus; mean GA at inclusion, 23 weeks and 65 measurements in group 2: 4-15 per fetus; mean GA at inclusion, 22 weeks. The estimated mean slopes of the MCA PSVs increased with the degree of postnatal therapy required (group 1: MCA PSV = 0.003 GA + 1.298; group 2: MCA PSV = 0.035 GA + 0.436). The relative average increments (RAI) were 4.7% and 7.1%, respectively. The two groups exhibited significant differences in mean slope and RAI (p<0.05)., Conclusions: Fetuses that required postnatal transfusions due to hemolytic disease showed an enhanced progressive increase in MCA PSVs compared to those without transfusion requirement. This information might enable their identification during pregnancy., (© 2014 Nordic Federation of Societies of Obstetrics and Gynecology.)

Objectives: The hemolysis of red blood cells due to isoimmunisation results in fetal anaemia and hypoxia leading to fetal heart failure. An assessment of N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a routine practice in adult heart failure. No studies on this marker have been reported in fetal heart failure. The aim of the current study was to investigate changes in fetal NT-proBNP serum concentrations before and after intrauterine transfusions and to assess its value as a marker of fetal heart failure., Design: Therapy of Rh immunisations was performed in 14 fetuses with 61 intrauterine transfusions. Hemoglobin concentration, red blood cells count, hematocrit and NT-proBNP concentrations were assessed in samples taken before and after each transfusion., Results: An increase in the concentrations of blood parameters was strongly correlated with a decrease in the concentration of NT-proBNP. NT-proBNP concentrations were the greatest with the smallest Hb (4.0-5.9 g/dl), hematocrit and red blood cell (RBC) concentrations, respectively. An increase in Hb concentration by 1mg/dl and the RBC count by 1M/µl resulted in a corresponding decrease in NT-proBNP concentration by 659.0 and 2 007.1 pg/ml, respectively. The NT-proBNP concentrations decreased significantly following 52 transfusions., Conclusions: The fetal serum concentration of NT-proBNP appears to be a satisfactory marker for heart failure in fetuses inflicted with severe anaemia caused by hemolytic disease. Intrauterine therapy decreases the severity of anaemia and reduces the fetal heart failure index. There appears to be a strong inverse correlation between the pre-transfusion NT-proBNP concentration and morphological parameters.

Objective: In this article, we will describe some of the special compatibility testing procedures and blood component preparation and modification techniques used in intrauterine and neonatal transfusion medicine. We also will review the transfusion therapy used in hemolytic disease of the fetus and newborn (HDFN) and fetal and neonatal alloimmune thrombocytopenia (FNAIT)., Finding: Transfusion therapy in the fetus and neonate requires blood typing and compatibility testing techniques not routinely used for adults. These include: cord blood testing, special attention to the volume and speed of infusion, cytomegalovirus risk reduction, and routine irradiation of cellular blood components. The treatment of HDFN and FNAIT involves phenotyping and/or genotyping of fetal and paternal red blood cells and platelets. In FNAIT, platelet products are chosen based on the absence of platelet-specific antigens., Conclusion: Fetal and neonatal transfusion medicine require special attention to the unique anatomic and physiologic features of early human development.

At present, rhesus prophylaxis concerns RhD negative pregnant women, even though 30 to 40% of them are bearing a RhD negative child. Knowing the RhD fetal genotype could change this quite irrational practice of prophylaxis (exposing many more women than needed to blood derived products) without reducing its efficacy. RhD fetal genotype determined on amniotic fluid has an excellent sensitivity. Presence of silent D genes slightly impairs its specificity which remains acceptable. However women have to be informed of possible false positives. Fetal RhD genotyping on maternal blood is more complex. Sensitivity is good from 10 GW and excellent after 15 GW. In case of a first negative result, it is recommended to control fetal RhD on a second sample drawn a few weeks later. Another new perspective for rhesus prophylaxis is the attempt to substitute polyclonal IgG anti-D into human monoclonal IgG anti-D. The main difficulty is to elaborate monoclonal antibodies with a capacity to neutralize RhD positive red blood cells equivalent to those of polyclonal anti-D. A new generation of antibodies is in process and preliminary clinical results are suggesting a possible use of these monoclonal antibodies for future rhesus prophylaxis but long-term follow-up is required to draw further conclusions.

The cloning of the RHD gene has made it possible to determine the RhD status of fetuses at risk for haemolytic disease due to RhD iso-immunization using amniotic fluid or chorionic villi-derived DNA and the polymerase chain reaction. However, some Rh haplotypes are associated with false-positive or negative DNA-based results with the potential for an adverse outcome. We determined the RhD status of a fetus using amniotic fluid-derived DNA for an anti-D iso-immunized woman. Initially, we obtained the ethnic background and the complete RhD and RhCcEe phenotypes of both parents. The mother was RhD negative (Cde/cde) but her DNA was positive for exon 10 of the RHD gene. The fetus was positive for both exons 4 5 and exon 10. Southern analysis confirmed that the maternal DNA contained a portion of the RHD gene with a restriction pattern that was similar to RhD-positive individuals. This report illustrates that, in addition to fetal DNA genotyping, the same PCR assays, complete with RhD and RhCcEe phenotypes, and ethnic background of the parents should be obtained to alert the molecular diagnostic laboratory to the presence of rare Rh haplotypes that are associated with DNA genotyping errors.

Objective: To study fetal erythroblasts (FE) from maternal peripheral blood for the diagnosis of fetal aneuploidies., Methods: FE expressing the glycophorin A(GPA) were isolated from 13 pregnant women with male fetus (8-14 w) by fluorescence-activated cell sorting(FACS), FE were identified by oligonucleotide primed in situ labelling (PRINS) with Y centromeric satellite DNA primer. The concentration of pregnancy-associated plasma protein A (PAPP-A) was measured by enzyme-labelled immunosorbent assay (ELISA) in serum samples of 41 normal pregnant women (8-14 w). In 5 pregnant women suspicious of fetal Down's syndrome (10-13 w) the serum and FE were examined by PAPP-A, GPA/FACS and PRINS with 21 chromosome centrometric primer., Results: Detection of flow sorted FE from 13 pregnant women by Y primer showed 14.5% of GPA positive signal. There was no difference in serum level of PAPP-A between 5 pregnant women and 41 normal controls, and all GPA positive cell nuclei of the 5 cases displayed two signals with 21 chromosome., Conclusion: Measurement of fetal erythroblasts from maternal blood for the diagnosis of genetic fetal aneuploidies is a promising non-invasive, rapid and reliable technique.

Thrombocytopenia, the most common hemostatic disease of the newborn, can now be safely identified and treated antenatally to prevent life-threatening fetal and neonatal hemorrhage. This article focuses on the fetal thrombocytopenias with emphasis on the most common causes, the immune thrombocytopenias, including alloimmune and autoimmune mechanisms. The clinical presentation and differential diagnosis are discussed briefly.

Fetal ascites is a rare ultrasonic diagnosis. The prognostic consequence is not clear. The course of pregnancy with fetal ascites in three cases is represented and compared with literature. The reason of fetal ascites often cannot be determined in spite of extensive diagnostic action. Problems of abortion are discussed.

The sinusoidal fetal heart rate pattern is significantly associated with severe fetal anaemia when seen in the antenatal period. Strict adherence to definition is important, as pseudosinusoidal patterns do not have the same grave prognostic significance. If this fetal heart rate pattern is seen antenatally it is our contention that the baby should be delivered urgently by Caesarean section, unless the fetal anaemia can be treated in utero.

Ultrasonically documented severe fetal ascites and hydrops resulted in complete, spontaneous antenatal resolution in two cases. Both of the deliveries were uncomplicated, and the outcome of the newborns was good.

Amniotic fluid a1-antitrypsin values were determined by radial immunodiffusion of 317 samples obtained between the 10th and 43rd weeks of gestation in normal pregnant patients and those with complications. Serial determinations of a1-antitrypsin values revealed that in normal patients values decreased as pregnancy advanced while values increased as pregnancy advanced in cases in which there was severe Rh-alloimmunization and hydramnios. A wide range of values was observed for each week of gestation. Although there was a definite tendency for values to decrease as pregnancy advanced (60.8 mg/100 ml before 30 weeks and 17.9/100 ml after 40 weeks); the method must be regarded as unreliable for determining fetal maturity in clinical practice. In the case of newborn infants with hyaline membrane disease, no decrease in amniotic fluid a1-antitrypsin values has been found.

Two cases of severe Rh-immunization are presented. The obstetric history, maternal serum anti-D titre, amniotic fluid spectrophotometric evaluation, amniography and ultrasound placentography suggest the diagnosis of hydrops fetalis. The reduction of fetal movements until cessation in the presence of an audible fetal heart point to a severely distressed fetus and impending death, thus providing additional data confirming the diagnosis of hydrops fetalis. The importance of diagnosed hydrops fetalis lies in the fact that most authors agree that in these cases treatment of the fetus should not be attempted.

Sonograms obtained during the 32nd and 34th weeks of a pregnancy complicated by severe Rh isoimmunization demonstrated features diagnostic of fetal-hydrops-scalp and body wall edema, ascites, hepatosplenomegaly and placental enlargement. The earliest sign that can be detected sonographically is placental enlargement.

Nonimmune hydrops fetalis may be associated with an elevated amniotic fluid delta OD450. Cases of I-cell disease (mucolipidosis II), lethal multiple pterygium syndrome, and alpha-thalassemia are presented, each associated with nonimmune hydrops fetalis and an elevated delta OD450. An elevated delta OD450 does not always indicate isoimmunization, and may be due to increased red blood cell turnover for a variety of reasons associated with nonimmune hydrops fetalis.

Ultrasound can be useful for fetal assessment in Kell-isoimmunized pregnancies. Because severe hydrops may develop within six days, ultrasound should be repeated more frequently than once per week even if the delta OD450 values are low.

The performance of 465 sonographically guided percutaneous umbilical blood samplings and its use in the management of diagnostic problems in the second and third trimester of pregnancy are described. The method has been employed in the prenatal assessment of 423 patients (357 procedures in the second trimester and 108 in the third trimester). Pure fetal blood was obtained in all third trimester samplings whilst in the second trimester in 4 cases (1.1%) fetal blood could not be obtained at the first procedure and in 9 cases (2.6%) contamination with maternal blood or amniotic fluid was observed. Data analysis confirm how this simple and rapid procedure offers access to the fetal circulation for diagnostic and therapeutic purposes.

The development of cordocentesis has permitted for the first time safe and direct evaluation of our second patient. The information garnered from the specimens obtained by cordocentesis will lay the groundwork for the development of primary-care fetal medicine--fetology.

Three cases of pregnancies complicated by feto-maternal anti-Kell iso-immunisation are presented, as well as a review of the literature. The evolution of new techniques for antenatal diagnosis has made it possible to have a new approach to this fetal pathology. Chorionic villus biopsy can be carried out in the first trimester of pregnancy when there has previously been a serious incidence of anti-Kell immunisation with a couple where the husband is heterozygous for the Kell antigen. In the second and third trimesters the surveillance of the patient is essentially dependent on ultrasound examination of the fetus and placenta, which makes it possible to detect hydropic changes, and also depends on blood sampling from the cord which makes it possible to assess by direct measurement the degree of fetal anaemia. Now pulsed Doppler must be added to these classical diagnostic techniques because it allows a gross estimation of fetal haematocrit levels.

In a referral perinatal center a detailed study was made of all the perinatal deaths that occurred during 1 year; they were analyzed according to primary diagnoses on the basis of a classification by R. L. Naeye which included the placenta. This method points to the areas in which special efforts at prevention should be made, and it should become a reliable basis for comparison.

The fetal blood erythroblast and reticulocyte counts were determined in umbilical cord samples obtained at 17 to 36 weeks' gestation from 127 pregnancies complicated by red blood cell isoimmunization. The reticulocyte count increased linearly with fetal anemia, and the erythroblast count increased exponentially. Significant erythroblastosis was observed only when the hemoglobin concentration deficit was greater than 7 gm/dl. Of the 52 fetuses with a hemoglobin concentration deficit greater than 7 gm/dl, 35 had ultrasonographic evidence of hydrops. These data suggest that medullary hematopoiesis is stimulated by mild anemia and that recruitment of extramedullary sites occurs when anemia is severe. Extensive hepatic erythropoiesis may be the cause of fetal hydrops in red blood cell isoimmunization.