Transient congenital hyperinsulinism and hemolytic disease of a newborn despite rhesus D prophylaxis: a case report.

BACKGROUND: In neonates, rhesus D alloimmunization despite anti-D immunoglobulin prophylaxis is rare and often unexplained. Rhesus D alloimmunization can lead to hemolytic disease of the newborn with anemia and unconjugated hyperbilirubinemia. In past reports, transient congenital hyperinsulinism has been described as a rare complication of rhesus D alloimmunization. Our case report illustrates that rhesus D alloimmunization can result in a pseudosyndrome with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia, despite correctly administered anti-D immunoglobulin prophylaxis. CASE PRESENTATION: We report of a 36-year-old, Caucasian gravida 1, para 1 mother with A RhD negative blood type who received routine antenatal anti-D immunoglobulin prophylaxis. Her full term newborn boy presented with severe congenital hyperinsulinism, anemia, and conjugated hyperbilirubinemia up to 295 µmol/L (ref. < 9), accounting for 64% of the total bilirubin. Syndromic congenital hyperinsulinism was suspected. Examinations showed a positive direct antiglobulin test, initially interpreted as caused by irregular antibodies; diffuse congenital hyperinsulinism by 18F-DOPA positron emission tomography/computed tomography scan; normal genetic analyses for congenital hyperinsulinism; mildly elevated liver enzymes; delayed, but present bile excretion by Tc99m-hepatobiliary iminodiacetic acid scintigraphy; and cholestasis and mild fibrosis by liver biopsy. The maternal anti-D titer was 1:16,000 day 20 postpartum. Y-chromosome material in the mother's blood could not be identified. This could, however, not exclude late intrapartum fetomaternal hemorrhage as the cause of immunization. No causative genetic findings were deetrmined by trio whole exome sequencing. The child went into clinical remission after 5.5 months. CONCLUSION: Our case demonstrates that rhesus D alloimmunization may present as a pseudosyndrome with transient congenital hyperinsulinism, anemia, and inspissated bile syndrome with conjugated hyperbilirubinaemia, despite anti-D immunoglobulin prophylaxis, possibly due to late fetomaternal hemorrhage.

Chelation therapy for secondary neonatal iron over load: Lessons learned from rhesus hemolytic disease.

Khdair-Ahmad F, Aladily T, Khdair-Ahmad O, Badran EF. Chelation therapy for secondary neonatal iron overload: Lessons learned from rhesus hemolytic disease. Turk J Pediatr 2018; 60: 335-339. Secondary neonatal iron overload occurs with intrauterine and post-natal blood transfusions. Treatment with intravenous Deferoxamine was reported only in four cases in the literature. Herein we report a case of a patient born at 36 weeks of gestation, who had rhesus hemolytic disease. He developed secondary iron overload, causing liver injury, after a total of six blood transfusions: four intrauterine and 2 post-natal transfusion therapies. Intravenous Deferoxamine treatment was started at the age of 45 days due to a ferritin level of 40,000 mg/L, progressive rise of liver enzymes, and worsening cholestasis. Treatment resulted in marked reduction in ferritin level (down to 829 mg/L at the age of 6 months), significant improvement in the liver enzymes, and resolution of cholestasis.

Bilateral cystic encephalomalacia following multiple intrauterine transfusions for anti-Kell isoimmunisation.

Fetal and neonatal haemolytic diseases result from maternal allo-immunisation to fetal antigens. Maternal antibodies cross the placenta causing red cell haemolysis, resulting in fetal anaemia and, in severe cases, hydrops and perinatal death. Intravascular intrauterine blood transfusion (IUT) has markedly reduced perinatal mortality and is now a standard procedure. IUT is considered to be a safe procedure with fetal loss rate reported to be less than 5% and no reported increase in the rate of neurodevelopment impairment. In this report, we are presenting a case of bilateral cystic encephalomalacia following fetal anaemia secondary to anti-Kell iso-immunisation treated with multiple IUTs. Such a significant adverse outcome following IUT for anti-Kell iso-immunisation has not been reported in the literature. This case highlights the need for appropriate parental counselling and routine postnatal head ultrasound in all babies delivered following multiple IUTs.

Mirror syndrome in a Chinese hospital: diverse causes and maternal fetal features.

OBJECTIVE: To investigate the clinical characteristics of mirror syndrome. METHODS: Retrospective analysis of cases with mirror syndrome. Data of clinical manifestations, laboratory examinations, placental morphology, treatment and prognosis of these patients were obtained and studied. RESULTS: Five cases satisfying the inclusion criteria for mirror syndrome were identified from our hospital database. The incidence of the condition was 0.0154% in China. Mirror syndrome was associated with Rhesus isoimmunization, intrauterine parvovirus B19 infection, fetal neuroblastoma, fetal heart malformation and unknown cause respectively. Fetal symptoms were multi-hydrocele and fetal heart failure complicating fetal hydrops. All of the cases manifested maternal hydrops and hemodilution, the other most common symptoms included hypertension, proteinuria, hypoalbuminemia, anemia, thrombocytopenia and elevated uric acid levels. Fetal outcomes in this study were poor with a perinatal mortality rate of 100%. Placentomegaly was observed in most cases and placental morphology showed villous edema, increased intervillous fibrin deposition and one rare case of fetal adrenal neuroblastoma. Resolution of maternal symptoms was noted within 3-30 days after delivery. CONCLUSION: Mirror syndrome is associated with a substantially increased risk of fetal death and severe maternal complications. Early diagnosis of this condition during pregnancy is crucial for providing proper treatments and achieving better clinical outcomes.

Anti-Rh(c), "little c," isoimmunization: the role of rHuEpo in preventing late anemia.

The overall prevalence of non-Rh-D isoimmunization seems to lie between 0.15% and 1.1%. Anti-Rh(c) alloimmunization, "little c," occurs in 0.07% of pregnancies and shows a quite broad clinical presentation. Late anemia is a frequent problem occurring in the setting of isoimmunization. It occurs more frequently after intrauterine blood transfusions or exsanguinotransfusion, and it can be thought as a hyporegenerative anemia. The authors describe the use of human recombinant erythropoietin in preventing late anemia in a case of anti-Rh(c) isoimmunization. The use of human recombinant erythropoietin is a valid tool for preventing late-onset anemia due to either anti-Rh-D or non-anti-Rh-D isoimmunization.

Gravedad del hidrops fetal por hemólisis Rh asociado con los resultados perinatales en transfusiones intrauterinas / Severe fetal hydrops in Rh hemolysis associated with perinatal results after intrauterine transfusions

Objetivo: Evaluar el grado de gravedad del hidrops fetal por isoinmunización materna Rh(D) y su repercusión sobre el resultado perinatal en una serie de casos de transfusión intrauterina. Material y método: Análisis retrospectivo, analítico y transversal de 150 fetos que recibieron 531 transfusiones intrauterinas en un período de 21 años. Todos presentaban un proceso evolutivo de gravedad y la presencia de hidrops previo al tratamiento se demostró en 67 fetos (45%), los cuales se clasificaron, de acuerdo con los hallazgos ultrasonográficos, como portadores de hidrops moderado o de hidrops grave. Las variables incluyeron edad gestacional, niveles de hemoglobina y hematocrito, número de transfusiones, tasas de supervivencia, la mortalidad acaecida por el procedimiento y las condiciones neonatales y evolutivas de los homigénitos. Resultados: Hubo 123 nacidos vivos (82%). Cuando no existió hidrops al inicio de la primera transfusión, la supervivencia global de los fetos que se presentaron con hidrops moderado fue del 76%, en tanto que los casos con hidrops grave fueron 52%. La reversión intrauterina del hidrops se documentó en el 81% de los fetos con hidrops moderado y en el 30% de aquellos con hidrops grave. La pérdida fetal como complicación durante el procedimiento fue baja. Condiciones neonatales pronósticas como el puntaje de Apgar a los 5 minutos y el peso obtenido fueron más favorables entre los fetos sin hidrops o con hidrops moderado que en los grados graves de afección hidrópica...

Desferrioxamine treatment of iron overload secondary to RH isoimmunization and intrauterine transfusion in a newborn infant.

Intrauterine transfusion is the standard of care in the management of severe Rh isoimmunization. Desferrioxamine has been used for the treatment of iron overload secondary to hemolysis and intrauterine transfusions in Rh isoimmunization cases. Here, we report a preterm infant born at 34 weeks of gestational age who had formerly received intrauterine transfusions for Rhesus hemolytic disease and presented with severe hyperferritinemia and elevated liver enzymes in the first week of life. Desferrioxamine treatment was started due to a ferritin level of 28,800 ng/ml and continued for 13 weeks. Although the treatment was successful, we observed resistant leukopenia which resolved after the cessation of treatment. In conclusion, iron overload secondary to intrauterine transfusions can be treated successfully with desferrioxamine; however, neonatologists must be aware of the possible side effects of this drug which has been used in only a limited number of newborns.

An elevated fetal interleukin-6 concentration can be observed in fetuses with anemia due to Rh alloimmunization: implications for the understanding of the fetal inflammatory response syndrome.

OBJECTIVE: The fetal inflammatory response syndrome (FIRS) has been described in the context of preterm labor and preterm prelabor rupture of the membranes and is often associated with intra-amniotic infection/inflammation. This syndrome is characterized by systemic fetal inflammation and operationally defined by an elevated fetal plasma interleukin (IL)-6. The objective of this study was to determine if FIRS can be found in fetuses with activation of their immune system, such as the one observed in Rh alloimmune-mediated fetal anemia. METHODS: Fetal blood sampling was performed in sensitized Rh-D negative women with suspected fetal anemia (n=16). Fetal anemia was diagnosed according to reference range nomograms established for the assessment of fetal hematologic parameters. An elevated fetal plasma IL-6 concentration was defined using a cutoff of >11 pg/ml. Concentrations of IL-6 were determined by immunoassay. Non-parametric statistics were used for analysis. RESULTS: (1) The prevalence of an elevated fetal plasma IL-6 was 25% (4/16); (2) there was an inverse relationship between the fetal hematocrit and IL-6 concentration -- the lower the hematocrit, the higher the fetal IL-6 (r=-0.68, p=0.004); (3) fetuses with anemia had a significantly higher plasma IL-6 concentration than those without anemia (3.74 pg/ml, interquartile range (IQR) 1.18-2.63 vs. 1.46 pg/ml, IQR 1.76-14.7; p=0.02); (4) interestingly, all fetuses with an elevated plasma IL-6 concentration had anemia (prevalence 40%, 4/10), while in the group without anemia, none had an elevated fetal plasma IL-6. CONCLUSIONS: An elevation in fetal plasma IL-6 can be observed in a subset of fetuses with anemia due to Rh alloimmunization. This observation suggests that the hallmark of FIRS can be caused by non-infection-related insults. Further studies are required to determine whether the prognosis of FIRS caused by intra-amniotic infection/inflammation is different from that induced by alloimmunization.

Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome.

INTRODUCTION: Mirror syndrome, also referred to as Ballantyne's syndrome, is normally defined as the development of maternal edema in association with fetal hydrops. The incidence of mirror syndrome is low and few cases have been published. We describe a case report in association with fetal Ebstein anomaly and provide a systematic review on the fetal associated conditions, maternal presentation and perinatal outcome reported for mirror syndrome. DATA SOURCES: A PubMed database search was done until December 2008 (English, French or German) without any restriction of publication date or journal, using the following key words: Ballantyne syndrome, Mirror syndrome, Triple edema, Pseudotoxemia, Maternal hydrops syndrome, Pregnancy toxemia, Acute second trimester gestosis, and Early onset preeclampsia. Reported cases were considered eligible when fetal associated conditions, maternal symptoms and fetal outcome were clearly described. RESULTS: Among 151 publications a total of 56 reported cases satisfying all inclusion criteria were identified. Mirror syndrome was associated with rhesus isoimmunization (29%), twin-twin transfusion syndrome (18%), viral infection (16%) and fetal malformations, fetal or placental tumors (37.5%). Gestational age at diagnosis ranged from 22.5 to 27.8 weeks of gestation. Maternal key signs were edema (80-100%), hypertension (57-78%) and proteinuria (20-56%). The overall rate of intrauterine death was 56%. Severe maternal complications including pulmonary edema occurred in 21.4%. Maternal symptoms disappeared 4.8-13.5 days after delivery. DISCUSSION: Mirror syndrome is associated with a substantial increase in fetal mortality and maternal morbidity.

Recombinant human erythropoietin in the prevention of late anemia in intrauterine transfused neonates with Rh-isoimmunization.

The majority of neonates with Rh-isoimmunization develops late anemia between the second and the sixth week of life. We report the effectiveness of recombinant human erythropoietin (rHuEPO) in preventing late anemia in 25 intrauterine and nonintrauterine-transfused neonates. The neonates were treated from 11+/-4 days after birth to 26+/-14 days (400 U/kg/d of rHuEpo, administered subcutaneously). During rHuEpo therapy, vitamin E, calcium folinate, and iron maltose were administered intramuscularly on a daily basis. Hematocrit, platelet, and neutrophil counts did not differ significantly before and after 21-days therapy. However, average values for reticulocyte showed a significant increase. The hematocrit values in the non-intrauterine transfusion (IUT) group increased progressively from the beginning to the end of the treatment, whereas that in the IUT group remained stable. Reticulocyte count increased during treatment in both groups, but it was significantly elevated in the non-IUT group only. Moreover, we observed that only neonates transfused with IUTs needed transfusions before and after treatment. This study suggests the effectiveness of rHuEpo therapy in the treatment of neonates with Rh-isoimmunization and it highlights how IUTs decrease the neonatal response efficacy. Larger, better if multicentric, randomized controlled trial are needed to definitely state whether rHuEPO safely decreases the incidence of late onset anemia.

Necrotizing enterocolitis following the use of intravenous immunoglobulin for haemolytic disease of the newborn.

AIM: To describe a series of patients who received intravenous immunoglobulin (IVIg) for the treatment of neonatal hyperbilirubinaemia and developed necrotizing enterocolitis (NEC) shortly thereafter. POPULATION AND RESULTS: We describe three healthy breastfed newly born infants with isoimmunization-derived hyperbilirubinaemia refractory to phototherapy who were treated with IVIg. Shortly after the perfusion finished they developed clinical and radiological signs compatible with NEC and needed antibiotic therapy, prolonged parenteral nutrition and even surgery in one case. Other conditions such as septicaemia or coagulopathy were ruled out. Microscopic examination of the resected intestine revealed the presence of disseminated thrombi obstructing multiple minor vessels of the mesenteric circulation. CONCLUSION: IVIg in the newborn period should be cautiously employed and always administered under strict medical control.

Valor de la flujometría Doppler de la arteria cerebral media en la predicción y seguimiento de la anemia fetal por isoinmunización Rh / Value of the middle brain artery Doppler flowmetry in the prediction and follow-up of fetal anemia due to Rh isoimmunization

La enfermedad hemolítica perinatal por isoinmunización Rh permanece como una de las causas más frecuentes de anemia fetal. La amniocentesis y la cordocentesis han sido usadas por muchos años para el diagnóstico y seguimiento de la anemia fetal. Estas técnicas son consideradas como invasivas y muchas complicaciones se asocian a su uso. El diagnóstico no invasivo de la anemia fetal se ha realizado a través de la ultrasonografìa Doppler. Basados en evidencia reciente, el estudio Doppler de la arteria cerebral media en su velocidad sistólica pico (ACM-VPS) podría evaluar con gran exactitud el grado de anemia fetal en la isoinmunizaciòn Rh. Esta prueba permite además el diagnóstico de la anemia fetal debido a otras etiologías, evita procedimientos invasivos innecesarios y por tanto, pudiera disminuir la morbilidad y mortalidad perinatales.

Perinatal hemolytic disease due to Rh isoimmunization is still one of the most common causes of fetal anemia. Amniocentesis and chordocentesis have been used for many years for the diagnosis and follow-up of fetal anemia. These techniques are considered as invasive, and many complications are associated with their use. The noninvasive diagnosis of fetal anemia has been made through Doppler ultrasonography. Based on recent evidence, middle cerebral artery peak systolic velocity (MCA-PSV) could evaluate with great accuracy the degree of fetal anemia in Rh isoimmunization. This test also allows the diagnosis of fetal anemia due to other etiologies, prevents the application of unnecessary invasive procedures and, therefore, may reduce perinatal morbidity and mortality.

Isoinmunización Rh: manejo de enfermedad hemolítica fetal severa / Rh-isoimmunization: severe immune hemolytic disease treatment

La enfermedad hemolítica perinatal (EHP), es definida como el desarrollo de anemia fetal o neonatal secundaria a un fenómeno hemolítico de tipo inmunológico. La causa de este síndrome se debe principalmente al desarrollo de isoinmunización materna. La EHP por el sistema Rh, suele ser severa, pero la incidencia ha disminuido dramáticamente en los últimos años debido a la instauración de la profilaxis RhoGAM (inmunoglobulina antiD) en mujeres Rh(-) no sensibilizadas. En el caso de generarse una enfermedad hemolítica fetal (EHF), el grado de anemia puede ser clasificado como leve, moderado o severo de acuerdo al valor de hemoglobina fetal según edad gestacional (EG) y al efecto fisiológico en el feto. El tratamiento de la EHF severa consiste en transfusión intravascular (TIV) y la pronta resolución del embarazo, si el feto es viable. Existen varios métodos para estimar la severidad de la enfermedad fetal. Entre éstos: medición de aglutininas anti Rh, medición de bilirrubina en líquido amniótico mediante espectrofotometría, ultrasonografía perinatal para identificar hidrops fetal (edema, ascitis, derrame), muestra sanguínea fetal obtenida mediante cordocentesis para medir hematocrito fetal directamente, y la ultrasonografía Doppler para medir la velocidad máxima de la arteria cerebral media (VmaxACM). En general la severidad de la EHF en un embarazo tiende a ser igual o más severa que los embarazos previos. Se presenta el caso de una paciente Rh(-) sensibilizada con antecedentes de dos mortinatos (29 y 30 semanas de gestación) por incompatibilidad Rh, y un prematuro de 28 semanas de gestación. La paciente es derivada a CERPO para manejo fetal y perinatal. Se decide control periódico mediante ultrasonografía Doppler con medición de la VmaxACM. Según el valor de ésta, en relación a la mediana para una EG dada, se realizaron transfusiones en tres oportunidades procediendo finalmente a la maduración pulmonar para una resolución a las 31+6 semanas de gestación. La ces...

Avaliar a correlação entre a concentração da hemoglobina e a medida ecográfica do diâmetro biventricular externo em fetos anêmicos de gestantes isoimunizadas / Assessment of the correlation between hemoglobin concentration and the echographic measurement of biventricular outer diameter in anemic fetuses of isoimmunized women

OBJETIVO: Verificar se existe correlação significativa entre a medida ecográfica do diâmetro biventricular externo e a concentração sérica da hemoglobina fetal pré-transfusional e se essa medida ecográfica poderá vir a ser utilizada como marcador não invasivo da anemia fetal. MÉTODOS: Estudo transversal prospectivo, no qual foram selecionadas 65 cordocenteses realizadas em 36 fetos anêmicos de mães portadoras de isoimunização pelo fator Rh. Obteve-se a medida do diâmetro biventricular externo (DBVE), por meio do modo M, utilizando-se aparelho de ultra-som convencional. Anterior à transfusão foi obtida amostra de 0,5ml de sangue fetal, para dosagem da hemoglobina, sendo a medida imediatamente realizada através de espectrofotometria, no equipamento Hemocue®. Como análise estatística foi utilizada a regressão dos mínimos quadrados, aceitando-se p<0,05 e análise multivariada. RESULTADOS: Foram observadas correlação inversa entre a concentração da hemoglobina no sangue fetal no momento prévio à transfusão e a medida do DBVE e correlação direta entre a medida do DBVE e a idade gestacional, e, também, através da análise multivariada que, à medida que a concentração de hemoglobina fetal cai, o DBVE aumenta, independentemente da influência da idade gestacional nesse parâmetro. CONCLUSAO: Existe correlação inversa entre a concentração da hemoglobina no sangue fetal e a medida do DBVE, independente da idade gestacional. Os achados sugerem que o DBVE poderá vir a ser um marcador ecográfico de predição do nível de hemoglobina de fetos de gestantes isoimunizadas.

Aloantígenos de granulocitos. Importancia clínica / The granulocyte alloantigens. Clinical importance

Los aloantígenos de granulocitos se agrupan en 2 grandes categorías: antígenos específicos de granulocitos y antígenos cuya distribución es más amplia y comprende otras líneas celulares. En 1998 se acordó establecer una nueva nomenclatura de los aloantígenos de granulocitos, basada en la localización glucoproteica de estos antígenos. La molécula FcgRIIIb es un miembro de la superfamilia de inmunoglobulinas (CD 16) en la cual se asientan varios de los aloantígenos específicos de granulocitos. Existen otros aloantígenos cuya función y localización se desconocen. Estas moléculas son de gran importancia clínica, pues se ven envueltas en una serie de enfermedades como la neutropenia neonatal aloinmune, cuyo carácter clínico moderado hace que pase inadvertida, la reacción febril no hemolítica, el daño pulmonar agudo relacionado con la transfusión, la neutropenia inmune asociada con el trasplante de médula ósea y la neutropenia autoinmune. Aunque se han producido avances en la caracterización de los aloantígenos de granulocitos, muchos puntos quedan sin aclarar, entre ellos, la significación clínica de muchos antígenos. El desarrollo creciente de técnicas moleculares, bioquímicas y serológicas para el estudio de los antígenos de células sanguíneas, nos permitirá aclarar los puntos que aún permanecen oscuros en este campo de la investigación

[Luteinized cystic ovarian hyperplasia during a normal pregnancy]. / Hyperplasie kystique lutéinisée des ovaires au cours d'une grossesse normale.

Hyperreactio luteinalis (HRL) is rarely observed in normal pregnancy. Its clinical spectrum consists of benign development of often bilateral lutein cysts and may be revealed by an overproduction of androgens. HRL is more often in relation with an excessive production of human chorionic gonadotropin (hCG) either in trophoblastic disease or in hyperplacentosis (Rh-alloimmunization or diabetes), but in 60% of the cases HRL may occur in normal singleton pregnancies. Many benign or malignant ovarian lesions can mimic HRL during pregnancy. The pathophysiology of HRL in singleton pregnancies involves an increased sensitivity of ovarian stromal cells to hCG. A positive ovarian stimulation test with hCG, recommended three months after delivery may detect a recurrence risk for further pregnancies. Conservative treatment is advised and surgery must be reserved for maternal complications.

Patient refusal of treatment in obstetrics.

During the later half of the previous century, Clinical Ethics evolved from the iconoclastic and murky realm of philosophical dissertation into a practical and useful discipline to be applied to clinical dilemmas occurring in everyday practice. We have explored a brief exposition of prevailing ethical theories that are most commonly recognized. These include Consequentialism and Principlism, and we have applied them to actual cases as they might occur in clinical practice. It is our hope that this will help us all to facilitate decisions with which we will be comfortable and which will be compatible with the beliefs and values of our patients.

Isoinmunización Rh: evaluación de la utilidad del Doppler de arteria cerebral media en la predicción y manejo de anemia fetal / Rh isoimmunization: evaluation of the utility of Doppler cerebral artery average in the prediction and handling of fetal anemia

Se presenta la experiencia en el manejo de pacientes altamente sensibilizadas por incompatibilidad Rh, analizando la utilidad de la evaluación de la velocidad circulatoria fetal, por Doppler-color, a través de la medición de la velocidad máxima sistólica (VMS) de la arteria cerebral media (ACM). Se realizan 19 transfusiones intravasculares en 3 casos afectados por esta enfermedad. En 14 de ellas se encontró anemia fetal moderada o leve, la que fue diagnosticada correctamente en 13 oportunidades, (92,8 por ciento) por la medición anteriormente señalada. Se encuentra una adecuada correlación entre la velocidad máxima sistólica de la arteria cerebral media y el grado de anemia fetal moderada o severa, con un índice correlacional (r= (_) 0,78). Se destaca el beneficio de un método no invasivo en el manejo de la anemia fetal de causa inmunológica o asociada a otras condiciones mórbidas y se abre un campo para futuras investigaciones.