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... Show moreSince 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. Show less
Ree, I.M.C.; Oever, R.M. van 't; Jansen, L.; Lopriore, E.; Haas, M. de; Klink, J.M.M. van 2021
Aim: To investigate the school performance and behavioral difficulties in children with hemolytic disease of the fetus and newborn (HDFN) treated with intrauterine transfusion (IUT) compared to... Show moreAim: To investigate the school performance and behavioral difficulties in children with hemolytic disease of the fetus and newborn (HDFN) treated with intrauterine transfusion (IUT) compared to Dutch norm data.Study design: Cros-sectional cohort study. Subjects: Children who received one or multiple IUTs for severe Rh-or K (Kell)-mediated HDFN between January 2008 and January 2015 at the LUMC.Outcome measures: School performance reports were assessed as well as behavioral difficulties as assessed with the Dutch child behavioral checklist (CBCL) by parents and caregivers and the Teacher Report Form (TRF) completed by teachers.Results: A response rate of 56% (70 children, aged 5-12 years) was obtained. Grade repetition occurred in 13 cases (19%), 16 children (23%) received some form of additional help, most often support by a speech therapist (n = 8), but also support for dyslexia (n = 4), physical therapy (n = 2) and social-emotional support (n = 2). None of the children in our study group attended special-needs education. School performance levels for reading comprehension, spelling and mathematics according to the Dutch National Pupil Monitoring System were similar for the study population and Dutch norm data. The incidence of behavioral problems as reported by parents was similar to the Dutch norm data, teachers reported less behavioral difficulties in the study group. Conclusion: This study shows favorable and reassuring school development in children treated with IUT in an experienced fetal-therapy center. A normal distribution in school and behavioral development is to be expected for children with HDFN treated with IUTs. Show less
Vos, T.W. de; Winkelhorst, D.; Haas, M. de; Lopriore, E.; Oepkes, D. 2020
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease in pregnancy characterized by maternal alloantibodies directed against the human platelet antigen (HPA). These antibodies can... Show moreFetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease in pregnancy characterized by maternal alloantibodies directed against the human platelet antigen (HPA). These antibodies can cause intracranial hemorrhage (ICH) or other major bleeding resulting in lifelong handicaps or death. Optimal fetal care can be provided by timely identification of pregnancies at risk. However, this can only be done by routinely antenatal screening. Whether nationwide screening is cost-effective is still being debated. HPA-1a alloantibodies are estimated to be found in 1 in 400 pregnancies resulting in severe burden and fetal ICH in 1 in 10.000 pregnancies. Antenatal treatment is focused on the prevention of fetal ICH and consists of weekly maternal IVIg administration. In high-risk FNAIT treatment should be initiated at 12-18 weeks gestational age using high dosage and in standard-risk FNAIT at 20-28 weeks gestational age using a lower dosage. Postnatal prophylactic platelet transfusions are often given in case of severe thrombocytopenia to prevent bleedings. The optimal threshold and product for postnatal transfusion is not known and international consensus is lacking. In this review practical guidelines for antenatal and postnatal management are offered to clinicians that face the challenge of reducing the risk of bleeding in fetuses and infants affected by FNAIT. Show less
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of thrombocytopenia in otherwise healthy newborns. During pregnancy, fetal blood cells enter the maternal circulation... Show moreFetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of thrombocytopenia in otherwise healthy newborns. During pregnancy, fetal blood cells enter the maternal circulation and might result in alloimmunization, the maternal production of antigen-specific alloantibodies. Once these alloantibodies enter the fetal circulation, they can cause damage. Clinical presentation can vary from an asymptomatic thrombocytopenia or relatively harmless bruises and petechiae to severe life-threatening and invalidating intracranial hemorrhages (ICHs). Once alloimmunization is detected and diagnosed, subsequent pregnancies can be treated to prevent the recurrence of bleeding complications. Unfortunately, in absence of population-based screening, alloimmunization is virtually only known after an affected fetus or newborn. Affected infants that might have been prevented if only the alloimmunization was known and treated prior to the occurrence of bleeding complications. Implementation of population-based screening in order to prevent FNAIT needs to be a carefully weighed decision. The benefits of screening need to outweigh the potential harm. To guide careful consideration and decision-making, Wilson and Jungner (W&J) proposed and published ten screening criteria. With this thesis, important evidence is presented that can be used for the fulfillment of the W&J criteria. Show less
Ree, I.M.C.; Smits-Wintjens, V.E.H.J.; Bom, J.G. van der; Klink, J.M.M. van; Oepkes, D.; Lopriore, E. 2017
Transfusion of red blood cells (RBCs) causes exposure to foreign antigens and, consequently, may induce alloimmunization. This research focused on identifying clinical determinants of RBC... Show moreTransfusion of red blood cells (RBCs) causes exposure to foreign antigens and, consequently, may induce alloimmunization. This research focused on identifying clinical determinants of RBC alloimmunization, eventually aiming to prevent alloimmunization by pre-emptively select extended matched blood for the predicted responder patient. Both RBC antigen intrinsic characteristics and patient-related factors were studied. Regarding antigen immunogenicity, K was confirmed to be the most potent antigen, followed by E, Cw, e, Jka and c. Of importance, anti-Jka is known to easily induce complement-mediated hemolysis. Inflammation due to severe bacterial and viral infections was associated to increased RBC alloimmunization incidences. Remarkably, although in line with murine models, Gram-negative bacteremia coincided with a twofold reduction of alloimmunization risk. In a non-hemoglobinopathy population, alloimmunization post-splenectomy was a highly unlikely event. Consequently, the Caucasian splenectomized patient does not benefit from RBC products matched beyond ABO/RhD. Patients with acute (either myeloid of lymphoblastic) leukemia, mature lymphomas, myelodysplastic syndrome, or patients post-autologous or -allogeneic stem cell transplantation demonstrated strongly reduced incidences of RBC alloimmunization, primarily explained by the intense immunosuppressive nature of treatments. Consequently, matching for the MDS population deserves renewed focus and should be based on the cumulative transfusion burden rather than on the diagnosis itself. Show less
Fetal anemia is a serious complication in pregnancy, and is associated with perinatal mortality and morbidity. One of the major advances in the management of fetal anemia was the introduction of... Show moreFetal anemia is a serious complication in pregnancy, and is associated with perinatal mortality and morbidity. One of the major advances in the management of fetal anemia was the introduction of the intrauterine blood transfusion (IUT). This thesis presents several studies on IUT for fetal anemia. We described current indications and complications of IUT, we analyzed contributing factors for adverse perinatal outcome and we showed learning curves of for this procedure. Furthermore, we report the long-term outcome after IUT in a large cohort of children (the LOTUS study). The vast majority (over 95%) of children treated with IUT for severe alloimmune anemia have a normal neurodevelopmental outcome, confirming the success of this antenatal treatment. From the studies described in this thesis, we conclude that after more than 20 years of improved knowledge and skills, IUT is to be considered a safe and successful method to treat severe fetal anemia for different causes. Show less
Lindenburg, I.T.M.; Kamp, I.L. van; Oepkes, D. 2014
The scope of the work described in this thesis is to examine whether potential transfusion related and clinical risk factors modulate the risk of alloimmunization in a general, previously not... Show moreThe scope of the work described in this thesis is to examine whether potential transfusion related and clinical risk factors modulate the risk of alloimmunization in a general, previously not transfused, non alloimmunized population of transfusion recipients. In these studies we emphasize the methodological aspects of observational research in clinical transfusion medicine Show less
This thesis focuses on several aspects related to the hematological outcome of infants with hemolytic disease of the fetus and newborn (HDFN) due to red blood cell alloimmunization, including... Show moreThis thesis focuses on several aspects related to the hematological outcome of infants with hemolytic disease of the fetus and newborn (HDFN) due to red blood cell alloimmunization, including pathogenesis and management of the disease. The presence of leukocytopenie and thrombocytopenia support the mechanism of suppression of thrombopoiesis and granulopoiesis in favor of the increased erythropoiesis stimulated by anemia and hypoxia. In addition to the problems caused by a shortage of platelets and white and red blood cells, the excess of the red blood cell metabolites bilirubin and iron also contribute to the morbidity of the disease. This thesis also contains a systematic review that demonstrates that there is lack of high level evidence promoting the use of intravenous immunoglobulin (IVIg) to prevent exchange transfusions in HDFN. Irrespective of the controversy concerning the use of IVIg, this thesis shows that intensive follow-up is indicated in both Rhesus D and non-Rhesus D HDFN and raised awareness about the associated morbidity is of paramount importance. Finally, this thesis also contains future research questions concerning HDFN. Show less
