Disease severity in subsequent pregnancies with RhD immunization: A nationwide cohort.

BACKGROUND AND OBJECTIVES: To evaluate the severity of haemolytic disease of the foetus and newborn (HDFN) in subsequent pregnancies with RhD immunization and to identify predictive factors for severe disease. MATERIALS AND METHODS: Nationwide prospective cohort study, including all pregnant women with RhD antibodies. All women with at least two pregnancies with RhD antibodies and RhD-positive foetuses were selected. The main outcome measure was the severity of HDFN in the first and subsequent pregnancy at risk. A subgroup analysis was performed for the group of women where RhD antibodies developed after giving birth to an RhD-positive child and thus after receiving anti-D at least twice (group A) or during the first pregnancy at risk for immunization (group B). RESULTS: Sixty-two RhD immunized women with a total of 150 RhD-positive children were included. The severity of HDFN increased for the whole group significantly in the subsequent pregnancy (p < 0.001), although it remained equal or even decreased in 44% of women. When antibodies were already detected at first trimester screening in the first immunized pregnancy, after giving birth to an RhD-positive child (group A), severe HDFN in the next pregnancy was uncommon (22%). Especially when no therapy or only non-intensive phototherapy was indicated during the first immunized pregnancy (6%) or if the antibody-dependent cell-mediated cytotoxicity result remained <10%. Contrarily, women with a negative first trimester screening and RhD antibodies detected later during the first pregnancy of an RhD-positive child (group B), often before they had ever received anti-D prophylaxis, were most prone for severe disease in a subsequent pregnancy (48%). CONCLUSION: RhD-mediated HDFN in a subsequent pregnancy is generally more severe than in the first pregnancy at risk and can be estimated using moment of antibody detection and severity in the first immunized pregnancy. Women developing antibodies in their first pregnancy of an RhD-positive child are at highest risk of severe disease in the next pregnancy.

Effective management of foetal anaemia in Rh(D) alloimmunised pregnant women with intrauterine transfusion: a Systematic Review.

BACKGROUND: Foetal anaemia is caused by a severe pregnancy complication, haemolytic disease of the foetus and newborn. Intrauterine transfusions (IUTs) are performed to treat foetal anaemia in alloimmunised pregnant women. If left untreated hydrops can develop thereby reducing the chance of survival. Survival rates have improved but the procedure is not without complications. Procedure-related complications can be associated with early gestational age, hence delaying IUT could improve outcomes. This review aims to determine the effectiveness and safety of IUTs by examining survival and mortality rates, procedure-related complications with associated foetal mortality and the influence of hydrops. STUDY DESIGN AND METHOD: A systematic review was conducted by searching keywords in four scientific databases from January 2000 to April 2022. A meta-analysis was performed with the OpenMeta-Analyst software using an arcsine transformed proportion with the binary random-effects model and maximum likelihood method. RESULTS: Fifteen studies were identified as eligible and used in the meta-analysis. The forest plots all showed statistically significant outcomes with heterogeneity of data. Results indicated a greater foetal survival rate with IUT to treat anaemic foetuses, a low foetal mortality rate, and low risk of procedure-related complications associated with foetal loss but a higher risk of foetal mortality when hydrops is present. CONCLUSION: The findings of this systematic review and meta-analysis provide evidence that IUT is a safe and effective treatment for foetal anaemia in the absence of hydrops when experienced personnel perform the procedure to minimise the risk of procedure-related complications.

Distribution of maternal red cell antibodies and the risk of severe alloimmune haemolytic disease of the foetus in a Chinese population: a cohort study on prenatal management.

BACKGROUND: Haemolytic disease of the foetus and newborn (HDFN) is the most common aetiology of haemolytic anaemia and hyperbilirubinaemia in foetuses and neonates. Studies on the distribution of antibodies that cause haemolytic disease of the foetus (HDF) in China are limited, and the effects of multiple antibodies on the severity of HDF need further evaluation. METHODS: An observational cohort study from January 2005 to December 2019 was conducted in two hospitals affiliated with Sun Yat-sen University. Maternal red cell alloimmunization was identified by the Guangzhou Blood Centre. In total, 268 pregnant woman-foetus pairs were divided into four groups according to the type of maternal alloantibodies: anti-D, anti-D combined with other antibodies, other single-antibody and other multiple antibodies. The obstetric history, antibody characteristics, incidence of severe HDF and foetal outcomes were collected and compared. Logistic regression analysis of the risk factors for HDF and survival analysis of the severe HDF-free interval were conducted. RESULTS: Anti-D was the most common cause of HDF, followed by anti-M. No anti-K- or isolated anti-c-associated HDF was found. The incidence of severe HDF was higher in the group with anti-D combined with other antibodies than in the group with anti-D alone (P = 0.025), but no significant difference was found in haemoglobin level and reticulocyte count in the anaemic foetuses between these two groups. Foetuses in the other single-antibody group had a lower reticulocyte count (P = 0.007), more IUTs (P = 0.007) and an earlier onset of severe HDF (P = 0.012). The maximum antibody titre was significantly lower in the other single-antibody group than in the anti-D group (P < 0.001). A high maternal antibody titre (P < 0.001), multiple affected pregnancies (P < 0.001) and other single-antibody (P = 0.042) were independent risk factors for HDF. A higher reticulocyte count (P = 0.041) was an independent risk factor for severe HDF in anaemia foetuses affected by Rh(D) alloimmunization. CONCLUSIONS: The distribution of HDF-associated antibodies in China is different from that in Western countries. Other single non-Rh(D) antibodies could increase the risk of HDF, and anti-D combined with other antibodies would not influence the severity of foetal anaemia compared with anti-D alone.

Perinatal outcomes of intrauterine transfusion for foetal anaemia due to red blood cell alloimmunisation.

The aim of this study was to evaluate the maternal and neonatal outcomes of patients who underwent intrauterine transfusion (IUT) for foetal anaemia due to red blood cell alloimmunisation and to determine the factors that affected the outcomes. All pregnancies that were treated with IUT due to Rh immunisation between January 2015 and June 2018 in the Kanuni Sultan Süleyman Training and Research Hospital, Department of Obstetrics and Gynaecology, were evaluated retrospectively. IUT due to non-Rh alloimmunisation, parvovirus B19 infection, chronic fetomaternal haemorrhage and foetal anaemia due to homozygous alpha-thalassemia were not included in the study. The perinatal and neonatal outcomes of the patients were retrospectively analysed. The gestational age, ultrasonography findings before and after IUT, laboratory results, complications related to IUT, and data on the newborns were recorded. The cases were divided into two groups, those with complication and those without complications, and their perinatal outcomes were compared. A total of 110 IUTs were performed in 42 foetuses. The survival rate after transfusion was 80.95%. Procedure-related complications were found in 12.7% of cases. There were no significant differences between the demographic and clinical characteristics of the patients with and without complications. The survival rate was lower and perinatal mortality was higher in foetuses with hydrops fetalis. IUT is a safe and effective procedure that can be used in the treatment of foetal anaemia in experienced centres. Survival rates can be increased by referring patients to experienced perinatology centres, by improving the IUT technique, and by reducing technique-related complications.Impact statementWhat is already known on this subject? The predominant use of IUT is to treat foetal anaemia due to red blood cell alloimmunisation. Despite the decrease after anti-D immune globulin prophylaxis, Rh immunisation is still a major cause of foetal anaemia. However, foetal survival rates have increased with the use of IUT.What do the results of this study add? The survival rates were increased after the development of a high-resolution ultrasound. Because foetal monitoring can be performed by ultrasonography, cord accidents and overload findings can be detected during transfusion, which allows for early interventions and increases survival rates.What are the implications of these findings for clinical practice and/or further research? The IUT procedure can be used in the treatment of foetal anaemia in experienced centres. After the technique was improved, the complication rates related to the procedure were decreased and foetal survival rates were increased. Further studies on the use of different IUT techniques will extend our findings.

Successful management of a hydropic fetus with severe anemia and thrombocytopenia caused by anti-CD36 antibody.

Cases of CD36 deficiency are not rare in Asian populations, foetal and neonatal alloimmune thrombocytopenia (FNAIT) caused by anti-CD36 isoantibodies appears more frequent than other HPA alloantibodies. However, little is known about the treatment of anti-CD36 mediated FNAIT in this region. A Chinese male foetus, whose mother had a history of multiple intrauterine foetal demise and/or hydrops, was diagnosed with severe FNAIT at 27 weeks of gestational age. Immunological analysis revealed total absence of CD36 on platelets and monocytes from mother, caused by a 329-330delAC mutation of the CD36 gene. Anti-CD36 and anti-HLA class I antibodies were detected in the maternal serum, whereas only anti-CD36 isoantibodies were detectable in the foetal blood sample. Serial intrauterine transfusions with red blood cells (RBC) and platelets from a CD36null donor were performed to improve the severe anaemia and thrombocytopenia. The baby (2250 g; Apgar scores 10) was delivered vaginally at 32 weeks of gestation with normal haemoglobin (186 g/L) but low platelet count (48 × 109/L). After 2 days the platelet count rose to 121 × 109/L. This report suggests that intrauterine transfusions with compatible RBC and CD36null platelets are useful in preventing the deleterious clinical effects of anti-CD36-mediated severe FNAIT.

Nivel de conocimientos de los obstetras acerca del diagnóstico y tratamiento de la isoinmunización materna: Estudio de corte transversal en Bogotá (Colombia), 2012-2013 / Level of knowledge among obstetricians regarding diagnosis and treatment of maternal isoimmunization: Cross-sectional study in Bogotá (Colombia), 2012-2013

Objetivo: describir el nivel de conocimientos acerca del diagnóstico, tratamiento y pronóstico de la isoinmunización materna entre los especialistas de Ginecología y Obstetricia afiliados a la Asociación Bogotana de Perinatología (ABP). Materiales y métodos: estudio descriptivo de corte transversal. Entre noviembre de 2012 y marzo de 2013, se aplicó una encuesta elaborada por especialistas en Medicina Materno-Fetal (MMF). Se excluyeron los profesionales que ejercen su actividad fuera del territorio nacional, aquellos que no han practicado la obstetricia durante los últimos diez años y a quienes no suministraron la totalidad de la información requerida. El instrumento estuvo compuesto por 18 preguntas organizadas en tres dominios: características sociodemográficas, información sobre la práctica clínica y conocimientos. Se utilizó estadística descriptiva para el análisis en la materia. Resultados: el instrumento se aplicó a 220 profesionales de los cuales 127 (57,7 %) respondieron la encuesta en su totalidad y fueron incluidos en el análisis. El 32 % de los obstetras y el 45 % de los especialistas en MMF identificaron correctamente el punto de corte para el coombs indirecto. El 43 y 62 % de los obstetras y especialistas en MMF reconocieron el papel de la velocimetría de la arteria cerebral media para el diagnóstico de anemia fetal, y el 82 y 76 % respectivamente la utilizarían en el seguimiento del feto anémico. Tan solo el 76 % de los obstetras y el 66 % de los especialistas en MMF reconocen las indicaciones de culminar la gestación en caso de anemia fetal, en tanto que el 90 y 97 % (respectivamente) identificaron cuándo realizar cordocentesis y transfusión in utero. Finalmente, el 37 % de los obstetras y el 48 % de los especialistas en MMF no reconocen a la curva de Queenan-Liley como una alternativa cuando no hay acceso al Doppler fetal. Conclusión: existe una importante variabilidad con respecto al nivel de conocimientos de los obstetras y especialistas en MMF en cuanto al diagnóstico, tratamiento y seguimiento de las gestantes con isoinmunización. Se requieren más estudios que caractericen la variabilidad en la práctica clínica acerca del diagnóstico y tratamiento de la isoinmunización materna en Colombia.

Objective: To describe the level of knowledge regarding the diagnosis, treatment and prognosis of maternal isoimmunisation among Gynaecology and Obstetrics specialists, members of ABP (Asociación Bogotana de Perinatología). Materials and methods: Cross-sectional descriptive study. A questionnaire prepared by specialists in Maternal and Foetal Medicine (MFM) was administered between November 2012 and March 2013. Professionals practicing outside the national territory, those who had not practiced over the past ten years, and those who did not provide all the information required were excluded. The tool consisted of 18 questions organized in three domains: socio-demographic characteristics, information about clinical practice, and knowledge of the subject. A descriptive statistical analysis was used. Results: Of the 220 practitioners who were given the questionnaire, 127 (57.7%) completed the survey and were included in the analysis. The cut-off point for the indirect Coombs was correctly identified by 32% of the obstetricians and by 45% of the specialists in MFM. The role of middle cerebral artery velocimetry for the diagnosis of foetal anaemia was recognized by 43% and 62% of obstetricians and specialists in MFM, and 82% and 76%, respectively, would use it for the follow-up of foetuses with anaemia. Only 76% of obstetricians and 66% of MFM specialists recognized the indications for delivering the baby in cases of foetal anaemia, whereas 90% and 97%, respectively, identified the timing for cordocentesis and in utero transfusion. Finally, 37% of obstetricians and 48% of MFM specialists did not recognize the Queenan-Liley curve as an option in cases where there is no access to foetal Doppler. Conclusion: There is an important variability in the level of knowledge among obstetricians and MFM specialists regarding the diagnosis, treatment and follow-up of pregnant women with isoimmunisation. Additional studies are required to characterize the variability in clinical practice regarding the diagnosis and treatment of maternal isoimmunisation in Colombia.

Determining the volume of blood required for the correction of foetal anaemia by intrauterine transfusion during pregnancies of Rh isoimmunised women.

BACKGROUND: Severe anaemic foetuses of Rhesus (Rh) isoimmunised mothers are usually treated by intrauterine transfusion (IUT). It is helpful to determine the volume of blood necessary to raise the concentration of haemoglobin by 1.0 g/dL in response to intrauterine transfusions. METHODS: In this cross-sectional, observational study we evaluated 107 first IUT for the correction of anaemia caused by haemolysis triggered by maternal Rh immunisation. The concentration of foetal haemoglobin was determined in umbilical cord blood before and after the IUT. The variation in foetal concentration of haemoglobin after transfusion was compared between groups of hydropic and non-hydropic foetuses, between groups of foetuses with different degrees of anaemia and with groups of gestational age less than or more than 28 weeks. The t-test for averages and ANOVA were used to compare average differences among the groups. p values less than 0.05 were considered statistically significant. RESULTS: Fifty-five (61.4%) foetuses were found to be anaemic while hydrops was observed in 40 (44%) at the time of the IUT. The volume of red blood cell concentrate infused varied from 5 to 90 mL, with 11.2±1.5 mL being necessary to raise the circulating concentration of haemoglobin by 1.0 g/dL. The foetal response was not influenced significantly by either the degree of foetal anaemia (p=0.56) or the presence of hydrops (p=0.17). The foetuses with a gestational age of 28 weeks or less required a smaller volume of red blood cell concentrate than those with a gestational age of more than 28 weeks (9.3±5.4 mL and 13.4±4.8 mL, respectively; p<0.0001) in order to raise their concentration of circulating haemoglobin by 1.0 g/dL. CONCLUSION: The volume of red blood cell concentrate necessary to correct anaemia in pregnancies complicated by Rh isoimmunisation must be considered carefully, since the response to the infusion of blood is peculiar in extremely premature infants. Hydrops and the degree of anaemia were not determinants of the change in the final concentration of circulating haemoglobin following the blood transfusion.

Aloinmunización RH: manejo anteparto. Revisión de la literatura / Antepartum management of rhesus alloimmunisation. A literature review

Introducción: la aloinmunización Rh es una enfermedad frecuente en Colombia pese al uso de inmunoglobulina anti-D(Rho) en los embarazos de alto riesgo. Asimismo, es una condición que requiere la identificación temprana de los factores de riesgo, así como el adecuado tamizaje con el fin de lograr una remisión oportuna a una unidad materno-fetal con experiencia para disminuir las complicaciones fetales y brindar la terapia indicada en caso de ser necesario. Objetivo: revisar la exactitud de los métodos de tamizaje y de diagnóstico temprano, así como también la efectividad de los métodos no invasivos e invasivos de tratamiento. Metodología: se realizó una revisión de la literatura existente de acuerdo con las bases de datos PubMed, EBSCO, Ovid y ProQuest desde el año 2000 hasta el 2008, la cual incluyó artículos de revisión e investigaciones originales. Resultados: la titulación de anticuerpos y el pico de velocidad máximo sistólico de la arteria cerebral media son las herramientas que permiten realizar la evaluación y la identificación de las pacientes en riesgo. El tratamiento incluye transfusión intrauterina y parto oportuno mientras que la prevención con la inmunoglobulina anti-D (Rho) continúa indicada. Conclusión: la aloinmunización Rh aún es una patología de interés en el control de las pacientes obstétricas de bajo y alto riesgo. El conocimiento que se obtenga de la enfermedad permitirá realizar el diagnóstico oportuno y, de esta manera, identificar los fetos en riesgo que son susceptibles de terapia intrauterina.

Introduction: rhesus alloimmunisation remains a common disease in Colombia in spite of universal immunisation having been implemented with immunoglobulin anti-D (Rho) for all susceptible pregnancies. Rh alloimmunisation is a condition requiring risk factors to be identified, all pregnancies to be suitably screened and timely referral to a maternal foetal medicine unit ensured to minimise foetal complications and provide foetal intervention as necessary. Objective: this review was aimed at summarising the available data to provide the reader with tools helping to improve medical care by reviewing the exactitude of screening methods and early diagnosis and the effectiveness of non-invasive and invasive methods of treatment. Methodology: the literature in PubMed, EBSCO, Ovid and Pro Quest databases was reviewed. Original papers, reviews, guidelines and bulletins published between 2000 and 2008 were included. Results: antibody titres and middle cerebral artery Doppler were seen to be the screening tools usually used for identifying haemolytic anaemia in the foetus and neonates in Rh alloimmunisation. Rh alloimmunization treatment included close follow-up, intrauterine transfusion and timely delivery and prevention of Rh alloimmunisation by immunoglobulin anti-D (Rho). Conclusion: knowledge of the disease will lead to early recognition of the risk factors and early diagnosis for identifying foetuses at risk which are susceptible to intrauterine therapy.

Management of Rh-isoimmunised Pregnancies : Our Experience.

BACKGROUND: The aim of this study was to assess the role of middle cerebral artery peak systolic velocity (MCA-PSV), as measured by doppler ultrasound, in detecting foetal anaemia in Rh- isoimmunised pregnancies. Intra-uterine foetal blood transfusion was performed in such anaemic foetuses to tide over the crisis of foetal immaturity till considered fit for extra-uterine survival. METHODS: Rh-isoimmunised pregnancies reporting to a tertiary institute from 2003 to 2005, were screened by doppler ultrasound to estimate MCA-PSV to detect foetal anaemia. If the foetus developed MCA-PSV of more than 1.5 multiple of median (MoM) for the gestational age, foetal blood sampling through cordocentesis was performed to confirm foetal anaemia, followed by intrauterine foetal blood transfusion to all anaemic foetuses at the same sitting. Neonatal outcome was evaluated by recording gestational age at the time of delivery, duration of gestational time gained and need for blood transfusion in the neonatal period. RESULTS: A total of thirteen isoimmunised pregnancies were evaluated. Three pregnancies did not require in-utero foetal blood transfusion. Twenty-one intrauterine foetal blood transfusions were performed in the remaining ten patients. Five received blood transfusion in the neonatal period. Intra uterine foetal death occurred in one grossly hydropic foetus and favourable neonatal outcome was recorded in the rest. CONCLUSION: The clinical outcome of these pregnancies justifies the use of doppler studies of MCA-PSV in detecting foetal anaemia and intra uterine foetal blood transfusion is the only hope of prolonging pregnancy and salvaging such foetuses.