Personalized treatment with immunoadsorption and intravenous immunoglobulin in a case of severe Rh alloimmunization during pregnancy unresponsive to plasma - exchange.

INTRODUCTION: Despite prophylaxis, a small proportion of RhD-negative women may develop anti-D antibodies after a sensitizing event occurring during pregnancy or delivery of a D-positive baby. Intrauterine transfusion (IUT) is the treatment of choice in case of fetal anemia, but it cannot be performed early during pregnancy. Combined treatment with therapeutic plasma-exchange (TPE) and intravenous immunoglobulin (IVIG) can avoid or delay IUT. Immunoadsorption (IA) could represent a more effective treatment in selected cases. CASE REPORT: We report a D-negative female with a history of induced abortion and hydrops fetalis, referred at 8 weeks of gestation with a high anti-D titer. Despite implementing a TPE-IVIG protocol, the patient experienced a spontaneous abortion. At the beginning of her fourth pregnancy, only after a partially effective intensive TPE course, cycles of IA-IVIG were performed. Despite a suboptimal response on the anti-D titer, Doppler ultrasonographic measurements of the fetal middle cerebral artery peak systolic velocity first showed evidence of anemia at 30 weeks of gestation and a IUT was required. After the IUT, anemia persisted with a subsequent dramatic rise in titer, requiring an emergent cesarean section. The infant subsequently underwent successful treatment with IVIG, phototherapy and exchange transfusion and was discharged 7 weeks later without neurological deficits. DISCUSSION: The treatment of high titer anti-D antibodies during pregnancy may require a multidisciplinary approach with utilization of different apheresis strategies in order to have a successful pregnancy outcome.

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.

Predictive factors of perinatal mortality in transfused fetuses due to maternal alloimmunization: what really matters?

INTRODUCTION: Alloimmunization is the main cause of fetal anemia. There are not many consistent analyses associating antenatal parameters to perinatal mortality in transfused fetuses due to maternal alloimmunization. The study aimed to determine the prognostic variables related to perinatal death. MATERIAL AND METHODS: A cohort study analyzed 128 fetuses treated with intrauterine transfusion (IUT), until the early neonatal period. Perinatal mortality was associated with prognostic conditions related to prematurity, severity of fetal anemia and IUT procedure by univariated logistic regression. Multiple logistic regression was used to compute the odds ratio (OR) for adjusting the hemoglobin deficit at the last IUT, gestational age at birth, complications of IUT, antenatal corticosteroid and hydrops. RESULTS: Perinatal mortality rate found in this study was 18.1%. The hemoglobin deficit at the last IUT (OR: 1.26, 95% CI: 1.04-1.53), gestational age at birth (OR: 0.53, 95% CI: 0.38-0.74) and the presence of transfusional complications (OR: 5.43, 95% CI: 142-20.76) were significant in predicting fetal death. CONCLUSION: Perinatal mortality prediction in transfused fetuses is not associated only to severity of anemia, but also to the risks of IUT and prematurity.

Patients treated with plasmapheresis: a case review from University Hospital of the Canary Islands.

INTRODUCTION: Plasmapheresis (PP) is a therapeutic apheresis technique used in the treatment of various renal and systemic diseases with varying degrees of proven clinical efficacy. OBJECTIVE: To review our experience with PP at the Hospital Universitario de Canarias, focused on effectiveness and safety results in different disease groups. MATERIAL AND METHODS: A retrospective-descriptive study of patients treated with PP from 01/01/2006 to 31/12/2009 at the hospital. We analysed medical histories and demographic data (sex, age), biochemical parameters, underlying disease, volume and type of replacement used in the PP sessions (5% human albumin and/or fresh frozen plasma), complications with the technique, delay in starting PP treatment after suspected clinical diagnosis, number of PP sessions received, patient mortality, degree of renal impairment and evolution of renal function. RESULTS: There were 51 patients studied, aged 50±18 years, of whom 60% were male; 331 PP sessions were performed. The diseases treated were grouped as: 11 vasculitis, 15 transplant immune activation, 5 haemolytic-uraemic syndrome (HUS), 7 idiopathic or thrombotic thrombocytopaenic purpura, 2 foetal Rh immunisations, 2 haematological diseases, 4 neurological diseases, among others. Overall mortality was 19.6% (n=10): 6 cases secondary to septic shock and the rest as a result of the evolution of the underlying disease, with 1 due to haemorrhagic shock in the renal biopsy area. There were no deaths in the transplant immune activation group. In the vasculitis group, there were 3 deaths (2 secondary to septic shock). Of the 10 patients who died, 9 did so within the first three months after diagnosis. Of the 26 renal biopsies performed, the most frequent indications were: vasculitis (23%), humoral rejection (42%), humoral rejection with calcineurin-inhibitor toxicity (12%) and HUS (8%), among others. Haemodialysis (HD) was required by 24 patients at the start of clinical symptoms: 9 of the 11 patients with vasculitis, 4 of the 5 patients with HUS and 5 of the 15 patients with transplant immune activation. At the end of evolution, 14 of them remained on the HD programme: 5 of the 11 patients with vasculitis, 2 of the 15 transplant patients and 3 of the 5 HUS patients. Significantly, patients who developed end kiney disease (EKD) in the vasculitis group were older and had higher creatinine at the onset of the disease. The transplant patients were monitored for anti-HLA class I or II before and after PP; there was a mean decrease of antibody titres in all but one patient; with an average decrease of 51% to 31%. In general, the PP technique was virtually free of complications. There were only 5 (3%) mild-moderate reactions to fresh plasma (perioral tingling and urticarial reactions) requiring pre-medication with steroids, but which did not lead to discontinuation of the treatment. CONCLUSION: Taking into account the wide variety of diseases that can benefit from PP and the nature of some of them, publishing our experience with this therapeutic method is of great importance. By increasing the description of case series by centre, we can add survival and renal function evidence in many uncommon diseases. Our study provides useful information for clinical practice and has also led us to reflect on future strategies to optimise outcomes in our patients.

Pediatric outcome in Rhesus hemolytic disease treated with and without intrauterine transfusion.

OBJECTIVE: To study the short-term morbidity in Rhesus hemolytic disease of infants treated either with or without intrauterine transfusions (IUT). STUDY DESIGN: All term and near term infants (gestational age > or = 36 weeks) with neonatal Rhesus hemolytic disease admitted to our center between January 2000-March 2005 were retrospectively included in the study. We recorded the duration of phototherapy, the need of exchange transfusions, and the need of top-up red blood cell transfusions until 6 months of age. RESULTS: A total of 89 infants were included, of whom 52 received at least one IUT. Duration of phototherapy in the IUT and no-IUT group was 3.8 and 5.1 days, respectively (P = .01). The percentage of infants requiring an exchange transfusion in the IUT group was 71% compared to 65% in the no-IUT group (P = .64). The percentage of infants requiring a top-up transfusion in the IUT and no-IUT group was 77% and 26.5%, respectively (P < .01). CONCLUSION: Infants with Rhesus hemolytic disease treated with IUT required less days of phototherapy and more top-up red blood cell transfusions than neonates without IUT. However, the need for exchange transfusion was similar in both groups.

Perinatal mortality in Rh alloimmunized patients.

OBJECTIVE: Evaluate and compare the perinatal mortality of Rh-negative pregnancies managed at São Paulo Federal University during a 9-year period, using either amniocentesis or middle cerebral artery peak systolic velocity. METHOD: Descriptive observational study involving 291 consecutive Rh-negative pregnancies managed between January 1995 and January 2004. The perinatal mortality of 99 alloimmunized patients was compared with 192 Rh-negative unimmunized patients (control group). The perinatal mortality of patients managed with amniocenteses was compared to those managed with Doppler studies. RESULTS: There were 74 patients managed with amniocenteses and 25 managed with Doppler studies. Perinatal mortality was significantly higher in the 99 Rh-negative isoimmunized patients than in the 192 unimmunized patients (12.1% versus 1%, p=0.0001) and did not differ according to the management protocol used (amniocentesis 13.5% versus cerebral Doppler 8.0%, p=0.725). Mean gestational age and mean weight at birth in pregnancies managed with amniocenteses (35.7 weeks and 2586 g) did not differ significantly from those managed with Doppler (36.3 weeks and 2647 g). CONCLUSIONS: Perinatal mortality in Rh-negative alloimmunized patients remains high and does not differ whether pregnancies are managed through amniocentesis or cerebral Doppler evaluation.

Diagnosis and management of Rh alloimmunization.

OBJECTIVE: To assess the current problem of alloimmunization in a tertiary referral center in Croatia. The results obtained were compared to data published worldwide. METHODS: Retrospective case analysis included women with Rhesus (Rh) alloimmunization treated in our department from January 1997 to January 2003. Data of interest included the incidence, prevention, diagnosis and treatment, with the final point being perinatal mortality and morbidity. RESULTS: 23 pregnant women with alloimmunization were identified. The incidence was 0.138% of deliveries in the same time period. The median gestational age at diagnosis/referral was 22 (range 9-37) weeks. Anti-D antigen, alone or in combination with the other antigens, was responsible for more than 90% of the alloimmunization cases included. A defined protocol for prevention of Rh D immunization after previous delivery was not followed properly in 9/19 cases. A particular problem was prophylaxis after previous pregnancy termination (TOP), whereby only 1/14 woman received adequate prophylaxis and only after 2 of 5 TOPs. Regarding fetal treatment, 9/23 women had a total of 24 intrauterine intravascular blood transfusions. Overall, perinatal mortality was 13%, and the median gestational age at delivery was 34 (range 31-40) weeks. In all there were 31 fetal exchange transfusions after delivery performed in 14/20 newborns. CONCLUSION: Despite precise diagnostic criteria and modern therapeutic options, alloimmunization remains a problem in Croatia. It is still related with a high perinatal mortality and morbidity. The main problem is inadequate prevention.

Fetal intravascular transfusion for hydropic disease due to rhesus isoimmunization.

OBJECTIVE: To evaluate the management of hydropic fetuses, due to rhesus isoimmunization, with fetal intrauterine intravascular transfusions. MATERIAL AND METHODS: This is a retrospective analysis of 18 rhesus-negative pregnant women presenting at our hospital with fetal hydrops during a 7-year period. All cases were managed with serial intrauterine intravascular transfusions with the goal of delivery by cesarean section beyond 33 weeks of gestation. All patients received prophylactic ampicillin and ritodrine for 4 days after the procedure. RESULTS: There were 11 mildly and 7 severely hydropic fetuses. All fetuses with mild hydrops and 5 of the 7 with severe hydrops were delivered alive after 32 weeks of gestation in a good condition. Two fetuses both with severe hydrops died in utero, at 28 weeks of gestation. Intrauterine reversal of hydrops occurred in 90.9% of fetuses with mild hydrops and in 57.1% of severely hydropic fetuses. CONCLUSIONS: The survival rate for the hydropic fetuses in our study was 88.9% and it was associated with the severity of fetal hydrops.

The effects of serial intravascular transfusions in ascitic/hydropic RhD-alloimmunized fetuses.

OBJECTIVE: To evaluate the effects of serial intravascular transfusions on RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion by measuring multiple hematological/biochemical blood variables. METHODS: Thirty-one singleton pregnancies were referred for management of RhD alloimmunization. Seven fetuses had hydrops on presentation and were transfused immediately. The remainder underwent weekly ultrasound examinations, and fetal blood sampling and transfusion were performed on development of ascites. In the 104 samples collected overall from the 31 fetuses, glucose, uric acid, urea, creatinine, total protein, total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase, alkaline phosphatase, lactic dehydrogenase, amylase, pseudocholinesterase (PCHE), creatine kinase, triglycerides and cholesterol were measured and compared with a reference range for non-anemic fetuses. RESULTS: The median gestational age at first transfusion was 26 (range, 18-34) weeks. There were three fetal losses after the first transfusion, two of which were due to procedure-related complications; one further loss occurred. At the first transfusion fetal hematocrit, pO2, total protein, PCHE, creatinine and urea concentrations were significantly decreased compared to reference data, while total and direct bilirubin, AST, ALT, amylase, triglyceride and uric acid concentrations were increased. In all surviving fetuses ascites/hydrops had disappeared by the second transfusion. Fetal pO2, total protein, AST, ALT and PCHE concentrations had normalized by the third transfusion. Correction of fetal anemia did not affect the other variables. CONCLUSIONS: RhD-alloimmunized fetuses with ascites/hydrops at the time of the first transfusion had a survival rate of 87%. Alterations of several biochemical fetal blood indices are present at the first sampling/transfusion, but most variables normalize with intravascular transfusions.

Intravenous fetal exchange transfusion before 22 weeks of gestation in early and severe red-cell fetomaternal alloimmunization.

OBJECTIVES: To determine the perinatal outcome in severe red-cell fetomaternal alloimmunization. METHODS: Retrospective series of 32 affected fetuses treated with intravenous fetal exchange transfusion (IFET) before 22 weeks of gestation. The main outcome measures were the degree of fetal anemia, fetal transfusions and perinatal outcome. RESULTS: The first IFET was performed at 19.8 +/- 1.8 weeks of gestation. All fetuses were severely anemic and hemoglobin levels were not different between 20 hydropic and 12 nonhydropic fetuses (4.1 +/- 2.5 vs. 5.6 +/- 2.8 g/dl, p=0.33). The initial maternal anti-D level ranged from 4 to 76 microg/l and was not correlated to fetal anemia (r=-0.07). CONCLUSION: The overall perinatal survival rate was 78% compared to a previous perinatal loss rate excluding first pregnancies of 55.5%.

Management of rhesus alloimmunization in pregnancy.

Hemolytic disease of the newborn secondary to rhesus alloimmunization was once a major contributor to perinatal morbidity and mortality. Today, rhesus immune globulin has markedly decreased the prevalence of this disease so that only one to six cases occur in every 1000 live births. The rarity of this condition warrants consideration of consultation or referral to a maternal-fetal medicine specialist. Once sensitization occurs, rhesus immune globulin is no longer effective. Evaluation for the presence of maternal anti-D antibody should be undertaken at the first prenatal visit. First-time sensitized pregnancies are followed with serial maternal titers and, when necessary, serial amniocenteses to detect fetal bilirubin by DeltaOD(450). In cases of a heterozygous paternal genotype, new deoxyribonucleic acid techniques now make it possible to diagnose the fetal blood type through amniocentesis or even from plasma/serum deoxyribonucleic acid analysis. When there is a history of an affected fetus or infant, maternal titers are no longer diagnostic as a screening test. Serial peak middle cerebral artery velocities using Doppler ultrasound can be used in these pregnancies to detect fetal anemia. In some situations, intrauterine transfusion is necessary through ultrasound-directed puncture of the umbilical cord with the direct intravascular injection of red cells. Perinatal survival rates of more than 90% have been reported; hydrops fetalis reduces the chance for a viable outcome by up to 25%. Immediate neonatal outcome is complicated by the need for repeated transfusions secondary to suppressed erythropoiesis. Long-term studies have revealed normal neurologic outcomes in more than 90% of cases. Future therapy will involve selective modulation of the maternal immune system making the need for intrauterine transfusions a rarity.

Epidemiología y causalidad de la mortalidad fetal intermedia y tardía / Epidemiology and causality of the intermediate and late fetal mortality

La mortalidad fetal se divide en intermedia (MFI), que ocurre entre las 20 y 27,6 semanas de edad gestacional, y tardía (MFT), que ocurre entre las veintiocho semanas de gestación y el término. El nacimiento de un feto muerto ocurre con una frecuencia del 0,5 al 1,2 por ciento de los nacimientos y la causa de muerte permanece indeterminada en alrededor del 20 por ciento de los casos. Se ha estimado que el 30 por ciento de las muertes fetales ocurren durante el trabajo de parto y el 70 por ciento restante durante el embarazo. El objetivo del presente estudio fue analizar su causalidad y elaborar propuestas tendientes a su disminución. Material y métodos: Diseño retrospectivo sobre la MFI y la MFT ocurrida en un período de diez años (1986-1996). La fuente de los datos fueron los formularios específicos de la División Estadística del Hospital Sardá. Las variables analizadas fueron: prevalencia de la MFI y la MFT, ingreso al servicio con feto vivo o muerto, muerte durante la internación, momento de producida la muerte fetal, edad gestacional al inicio del control prenatal, peso fetal apróximado al momento de la muerte fetal, presencia maceración fetal, presencia de malformaciones fetales, diagnóstico de patología asociada al embarazo y diagnóstico anatomo-patológico. Las muertes fueron agrupadas según la clasificación de Baird y la clasificación de Wigglesworth modificada por Althabe. Análisis estadístico: test de Chi cuadrado y Kruskal-Wallis. Resultados: En los diez años analizados se registraron 72.081 nacimientos. De estos 1.126 nacieron muertos (1,56 por ciento), divididos en 1.044 con 500 g de peso al nacer o más y 706 casos de 1.000 g o más. No se obtuvieron datos de 32 casos por lo que la muestra total a analizar es de 1.094 fetos muertos con 500 g o más de peso al nacer. La mortalidad fetal global (>500 g) fue de 14,48/1.000 RN y la MFT de 9,79/1.000 RN. Se describe la población de fetos muertos según peso al nacer, estado fetal al ingreso al hospital, momento de producida la muerte fetal en relación al trabajo de parto, frecuencia de controles prenatales, edad materna, frecuencia de la mortalidad fetal según intervalos de peso, forma de terminación del embarazo, causa clínica de mortalidad fetal, distribución de causa de muerte fetal según la clasificación de Baird y Wigglesworth. Conclusión: La mortalidad fetal tiene una estrecha relación con la falta de control prenatal...

Epidemiología y causalidad de la mortalidad fetal intermedia y tardía / Epidemiology and causality of the intermediate and late fetal mortality

La mortalidad fetal se divide en intermedia (MFI), que ocurre entre las 20 y 27,6 semanas de edad gestacional, y tardía (MFT), que ocurre entre las veintiocho semanas de gestación y el término. El nacimiento de un feto muerto ocurre con una frecuencia del 0,5 al 1,2 por ciento de los nacimientos y la causa de muerte permanece indeterminada en alrededor del 20 por ciento de los casos. Se ha estimado que el 30 por ciento de las muertes fetales ocurren durante el trabajo de parto y el 70 por ciento restante durante el embarazo. El objetivo del presente estudio fue analizar su causalidad y elaborar propuestas tendientes a su disminución. Material y métodos: Diseño retrospectivo sobre la MFI y la MFT ocurrida en un período de diez años (1986-1996). La fuente de los datos fueron los formularios específicos de la División Estadística del Hospital Sardá. Las variables analizadas fueron: prevalencia de la MFI y la MFT, ingreso al servicio con feto vivo o muerto, muerte durante la internación, momento de producida la muerte fetal, edad gestacional al inicio del control prenatal, peso fetal apróximado al momento de la muerte fetal, presencia maceración fetal, presencia de malformaciones fetales, diagnóstico de patología asociada al embarazo y diagnóstico anatomo-patológico. Las muertes fueron agrupadas según la clasificación de Baird y la clasificación de Wigglesworth modificada por Althabe. Análisis estadístico: test de Chi cuadrado y Kruskal-Wallis. Resultados: En los diez años analizados se registraron 72.081 nacimientos. De estos 1.126 nacieron muertos (1,56 por ciento), divididos en 1.044 con 500 g de peso al nacer o más y 706 casos de 1.000 g o más. No se obtuvieron datos de 32 casos por lo que la muestra total a analizar es de 1.094 fetos muertos con 500 g o más de peso al nacer. La mortalidad fetal global (>500 g) fue de 14,48/1.000 RN y la MFT de 9,79/1.000 RN. Se describe la población de fetos muertos según peso al nacer, estado fetal al ingreso al hospital, momento de producida la muerte fetal en relación al trabajo de parto, frecuencia de controles prenatales, edad materna, frecuencia de la mortalidad fetal según intervalos de peso, forma de terminación del embarazo, causa clínica de mortalidad fetal, distribución de causa de muerte fetal según la clasificación de Baird y Wigglesworth. Conclusión: La mortalidad fetal tiene una estrecha relación con la falta de control prenatal...(AU)

Survival analysis of transfused fetuses affected by Rh-alloimmunization.

The aim of the present study was to evaluate the survival rate of a group of 86 fetuses affected by Rh-alloimmunization submitted to intrauterine red blood cell transfusion. All the women had antibody titres> or = 1:32 at the time of their enrollment in the study. Crude fetal survival rate was 89.5% (77/86 cases). Data were stratified according to specific cut-off points of (1) pre-transfusion fetal haemoglobin expressed as the rate between the observed and the estimated value for each gestational age at the time of the first transfusion; (2) the difference between the haemoglobin at the beginning of the second-transfusion less that at the end of the first transfusion (delta haemoglobin); and (3) presence of ultrasound detected anomalies. Statistically significant stratification of the survival rate was observed for the level of pre-transfusion fetal haemoglobin (95% and 76.9%, respectively, p= 0.009) using a cut-off value of < 70% and > or = 70% of the expected value. Again, delta haemoglobin showed a different survival rate when a cut-off value of 6 g/dl was used to generate subgroups of fetuses: 94.6% and 80%, respectively (p= 0.0145). Among the ultrasound anomalies, the presence of hydrops showed a correlation with the survival rates. The quoted values were 97.83% (absence) and 80.0% (presence) respectively (p= 0.0058). Cox regression showed a significant association of the studied variables with the outcome (survival). The presence of hydrops was the best predictor (Odds ratio= 8.7, p= 0.0073) followed by Delta haemoglobin (Odds ratio= 2.0, p= 0.0422). The rate of pre-treatment fetal haemoglobin < 70% of the expected value did not add any significant valu and was thus removed from the final model. Weight at delivery expressed in grams showed a direct correlation with the survival rate (Odds ratio= 0.9, p= 0.1529) and was added into the model as an adjustment quantitative variable.

Rhesus disease: postnatal management and outcome.

The incidence of rhesus haemolytic disease has been markedly reduced. Affected infants who have had intrauterine transfusions suffer a late hyporegenerative anaemia. Postnatal haemolysis and hence treatment for hyperbilirubinaemia is less commonly needed. Optimal phototherapy reduces the need for postnatal exchange transfusions, but data on the efficacy of inhibitors of bilirubin production such as haem oxygenase inhibitors or immunoglobulin are less secure. Even hydropic infants have less than 20% mortality and bilirubin encephalopathy is uncommon. There is, however, very limited information on the long-term outcome of infants with rhesus haemolytic disease. Multicentre collaboration is required to test strategies to improve the management of affected individuals further and to provide meaningful data on their prognosis.

[Management of Rhesus isoimmunization. Viewpoint of the obstetrician]. / Prise en charge de l'iso-immunisation Rhésus. Vue de l'obstétricien.

Although rare, severe forms of Rhesus isoimmunization are still observed. Early diagnosis and treatment with intrauterine transfusions allow an 80% survival rate. Anti-D alloimmunizations usually result from missed prophylaxis with anti-D serum at delivery, thus underlying the need for a rigorous application of this prophylaxis.