Rh Alloimmunisation: Current Updates in Antenatal and Postnatal Management.

In spite of advances in medical science, Rh alloimmunisation remains one of the leading causes of preventable neuro-morbidities and significant neonatal hyperbilirubinemia in lower-middle income countries. Despite availability of effective antenatal preventive strategy (Anti-D), its uptake in antenatal period is low due to ignorance. Further, once diagnosed, there is lack of adequate antenatal follow up in health care facility. Some of these cases even remain undiagnosed in antenatal period only to present as a case of severe hyperbilirubinemia and kernicterus in late neonatal period. Thus, there is an urgent need for creating awareness and educating health care professionals for early detection and timely management in both antenatal and postnatal period. Following two doses of anti-D prophylaxis (one in antenatal period and one in immediate postnatal period) the incidence of Rh alloimmunisation can reduce to <1%. It is recommended to follow all Rh alloimmunised pregnancies antenatally with serial indirect Coombs test titre (till critical titre is reached) followed by serial Doppler velocimetry of middle cerebral artery in a perinatal centre where facility for intrauterine transfusion as well as advanced neonatal care is available. Postnatal management of these infants comprises of confirmation of diagnosis, aggressive phototherapy and in selective cases, double volume exchange transfusion. With appropriate antenatal and postnatal management, the prognosis of Rh alloimmunised pregnancy remains favourable and long term outcome of Rh alloimmunised infants remain comparable with their normal counterparts.

Rhesus D alloimmunization in pregnancy from 1996 to 2015 in Iceland: a nation-wide population study prior to routine antenatal anti-D prophylaxis.

BACKGROUND: Rhesus D (RhD) incompatibility is still the most important cause of hemolytic disease of the fetus and newborn (HDFN) worldwide. The aim of this study was to investigate the incidence, causes, and consequences of anti-D alloimmunizations in pregnancy in Iceland, prior to implementation of targeted routine antenatal anti-D prophylaxis (RAADP) in 2018. STUDY DESIGN AND METHODS: This was a nation-wide cohort study of 130 pregnancies affected by RhD alloimmunization in Iceland in the period from 1996 through 2015. Data were collected from transfusion medicine databases, medical records, and the Icelandic Medical Birth Register. RESULTS: Of 130 RhD alloimmunizations, 80 cases (61.5%) represented new RhD immunization in the current pregnancy. Sensitization was discovered in the third trimester in 41 (51.3%) and occurred in the first pregnancy in 14 cases (17.5%). The most likely causative immunization event was the index pregnancy for 45 (56.25%), a previous pregnancy/birth for 26 (32.5%), abortion for 3 (3.75%), and unknown for 6 women (7.5%). Higher anti-D titers were associated with shorter gestational length, cesarean sections, positive direct antiglobulin test (DAT), and severe HDFN. Intrauterine transfusion (IUT) was performed in five pregnancies (3.8%), and 35 of 132 (26.5%) live-born neonates received treatment for HDFN; 32 received phototherapy (24.2%), 13 exchange transfusion (9.8%), and seven simple blood transfusion (5.3%). CONCLUSION: In about half of cases, RhD alloimmunization was caused by the index pregnancy and discovered in the third trimester. Thus, the newly implemented RAADP protocol should be effective in reducing the incidence of RhD immunization in Iceland in the future.

Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women - outcome of the first two years of a national program in Finland.

INTRODUCTION: The aim of this study was to assess the accuracy of the non-invasive fetal RHD test at 24-26 weeks of gestation as part of the national antenatal screening program to target routine antenatal anti-D prophylaxis (RAADP) at 28-30 weeks at women carrying an RhD-positive fetus. MATERIAL AND METHODS: A prospective cohort study involving all maternity care centers and delivery hospitals in Finland between February 2014 and January 2016. Fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed with real-time polymerase chain reaction in a centralized setting. The results were systematically compared with the serological newborn RhD typing. The main outcome measure was the accuracy of the fetal RHD assay; the secondary variable was compliance with the newly introduced RAADP program. RESULTS: Fetal RHD was screened from 10 814 women. For the detection of fetal RHD, sensitivity was 99.99% [95% confidence interval (CI) 99.92-99.99] and specificity 99.81% (95% CI 99.60-99.92). One false-negative and seven false-positive results were reported by the delivery hospitals in two years. The negative predictive value of the test was 99.97% (95% CI 99.81-99.99). At the end of the study period, over 98% of the RhD-negative women participated in the new screening program. CONCLUSIONS: The targeted RAAPD program was implemented effectively in the national maternity care program in Finland. An accurate fetal RHD screening test allows discontinuation of newborn testing without risking the postnatal prophylaxis program. In the future, the main area to investigate will be the clinical effect of RAADP on subsequent pregnancies.

Third trimester screening for alloimmunisation in Rhc-negative pregnant women: evaluation of the Dutch national screening programme.

OBJECTIVE: To evaluate the effect of red blood cell (RBC) antibody screening in the 27th week of pregnancy in Rhc-negative women, on detection of alloimmunisation, undetected at first trimester screening ('late' alloimmunisation), and subsequent haemolytic disease of the fetus and newborn (HDFN), to assess risk factors for late alloimmunisation. DESIGN: Prospective cohort and nested case-control study. SETTING: The Netherlands. POPULATION: Two-year nationwide cohort. METHODS: Prospective inclusion of Rhc-negative women with negative first trimester screening and of screen-negative controls. Assessment of incidence and numbers needed to screen (NNS) of late alloimmunisation and HDFN; logistic regression analysis to establish risk factors for late alloimmunisation. MAIN OUTCOME MEASURES: Late alloimmunisation, HDFN. RESULTS: Late alloimmunisation occurred in 99 of 62 096 (0.159%) Rhc-negative women; 90% had c/E antibodies and 10% non-Rhesus antibodies. Severe HDFN (fetal/neonatal transfusion) occurred in two of 62 096 (0.003%) of Rhc-negative women and 2% of late alloimmunisations; moderate HDFN (phototherapy) occurred in 20 children [22.5%; 95% confidence interval (CI), 13.8-31.1%]. Perinatal survival was 100%. The NNS to detect one HDFN case was 2823 (31 048 for severe, 3105 for moderate HDFN). Significant risk factors were former blood transfusion [odds ratio (OR), 10.4; 95% CI, 1.14-94.9], parity (P-1: OR, 11.8; 95% CI, 3.00-46.5; P > 1: OR, 7.77; 95% CI, 1.70-35.4) and amniocentesis/chorionic villus sampling during current pregnancy (OR, 9.20; 95% CI, 1.16-72.9). CONCLUSIONS: Additional screening of Rhc-negative women improved the detection of late alloimmunisation and HDFN, facilitating timely treatment, with a NNS of 2823. Independent risk factors for late alloimmunisation were blood transfusion, parity and chorionic villus sampling/amniocentesis in the current pregnancy. The occurrence of most factors before the current pregnancy suggests a secondary immune response explaining most late alloimmunisations. TWEETABLE ABSTRACT: Third trimester screening for alloimmunisation in Rhc-neg women improves detection and treatment of severe HDFN.

Enfermedad hemolítica perinatal causada por anticuerpos anti-M y tratada con inmunoglobulinas intravenosas fetales / Hemolytic disease of the fetus due to anti-M antibodies treated with fetal intravenous immunoglobulin therapy

Presentamos el caso de una mujer de 28 años, con 2 abortos tardíos previos causados por anticuerpos anti-M. En la actual gestación es tratada desde la semana 23 hasta la semana 34 con inmunoglobulinas intravenosas fetales, con resultado satisfactorio. Aunque no hay estudios randomizados y controlados que indiquen que las inmunoglobulinas fetales son efectivas en el manejo de la isoinmunización, pequeñas series de casos sugieren resultados prometedores (AU)

We present the case of a 28-year-old woman with two prior late miscarriages caused by anti-M antibodies, leading to alloimmunization of her previous pregnancies. During this pregnancy, she was successfully treated with intravenous immunoglobulins administered from the 23th to the 34th week of pregnancy. There are no randomized trials to indicate whether the antenatal use of intravenous immunoglobulin is effective in the management of fetal red blood cell alloimmunization. Several case series suggest a beneficial role in preventing severe fetal anemia (AU)

Aportación del Doppler de la arteria cerebral media y del genotipado RHD fetal en el manejo de la isoinmunización / Contribution of middle cerebral artery Doppler and fetal RHD genotype in the management of alloimmunization

Objetivo. Evaluar la aplicación clínica de los métodos no invasivos en el manejo de la isoinmunización, durante el período de 2006-2010. Sujetos y métodos. Se estudiaron 70 gestaciones con riesgo de anemia fetal en las que se realizó el estudio Doppler de la velocidad sistólica de la arteria cerebral media (VS-ACM). Se comparó la eficacia de la VS-ACM después de una, 2 o 3 transfusiones intrauterinas. El genotipado fetal RHD en sangre materna se realizó en las gestaciones seguidas en nuestro centro. Resultados. Se practicó cordocentesis en 22 de gestaciones y en 20 se practicó transfusión intrauterina. Las tasas de detección y de falsos positivos de la VS-ACM en la predicción de anemia fetal moderada o severa fueron del 89 y el 15% en gestaciones sin transfusión previa, del 100 y el 41% en los casos con una transfusión previa y del 40 y el 24% cuando se practicaron más de una transfusión. Conclusiones. La VS-ACM mantiene una sensibilidad alta en una transfusión previa aunque su especificidad disminuye (AU)

Objective. To assess the clinical application of non-invasive methods in the management of alloimmunization from 2006 to 2010. Subjects and methods. Seventy pregnancies with risk of fetal anemia were studied by fetal middle cerebral artery peak systolic velocity (MCA-PSV). The efficacy of MCA-PSV was compared between the first, second and third transfusions. Prenatal testing of fetal RHD blood group using maternal blood was performed in pregnancies followed-up in our center. Results. Fetal blood sampling was performed in 22 pregnancies; of these, fetal transfusion was carried out in 20. Detection rates and the false-positive rate of MCA-PSV in the prediction of severe or moderate fetal anemia were 89% and 15% in pregnancies with no previous transfusions, 100% and 41% in patients with one previous transfusion, and 40% and 24% when more than one transfusion was performed. Conclusion. MCA-PSV has high sensitivity when there is one previous fetal transfusion but its specificity is lower (AU)

Cholestasis in neonates with red cell alloimmune hemolytic disease: incidence, risk factors and outcome.

BACKGROUND: Etiology of cholestatic liver disease in neonates with hemolytic disease of the newborn (HDN) has been associated with iron overload due to intrauterine red cell transfusions (IUTs). Data on the incidence and severity of cholestasis in neonates with HDN are scarce, and little is known about pathogenesis, risk factors, neonatal management and outcome. OBJECTIVE: To evaluate incidence, risk factors, management and outcome of cholestasis in neonates with red cell alloimmune hemolytic disease. METHODS: All (near-) term neonates with HDN due to red cell alloimmunization admitted to our center between January 2000 and July 2010 were included in this observational study. Liver function tests (including conjugated bilirubin) were routinely performed in the neonatal period. We recorded the presence of cholestasis, investigated several potential risk factors and evaluated the management and outcome in affected neonates. RESULTS: A total of 313 infants with red cell alloimmune hemolytic disease treated with or without IUTs were included. The incidence of cholestasis was 13% (41/313). Two risk factors were independently associated with cholestasis: treatment with at least one IUT (OR 5.81, 95% CI 1.70-19.80, p = 0.005) and rhesus D type of alloimmunization (OR 4.66, 95% CI 1.05-20.57, p = 0.042). Additional diagnostic tests to investigate possible causes of cholestasis were all negative. In 5 infants (12%), supportive medical and nutritional therapy was started, and one neonate required iron chelation therapy. CONCLUSION: Cholestasis occurs in 13% of neonates with HDN due to red cell alloimmunization, and it is independently associated with IUT treatment and rhesus D type of alloimmunization.

[Fetomaternal anti-RH3, -4 (anti-E and anti-c) rhesus isoimmunization: a case report]. / Allo-immunisation fœto-maternelle rhésus anti-RH3, 4 (anti-E et anti-c) : à propos d'un cas.

Hemolytic disease of the newborn caused by maternal isoimmunization has been decreasing over the past 10 years because of prophylactic treatment with anti-RH1 (anti-D) immunoglobulin. Nevertheless, there is an increase in the incidence of both relative and absolute numbers of non-RH1 red-cell maternofetal isoimmunizations, essentially anti-RH4 (anti-c), anti-RH3 (anti-E), and anti-Kell. In 8 to 14% of cases, multispecificity antibodies are present, the most common combination being the association of anti-RH3 and -4. Despite absence of specific prophylactic therapy, anti-RH4 isoimmunization could be as severe as anti-RH1 ; as for anti-RH3, it is usually associated with mild to moderate clinical manifestations. Nevertheless, there are few publications on anti-RH3, -4 maternofetal isoimmunization with a bias toward the most severe cases being reported. We report here a case of nonsevere maternofetal anti-RH3, -4 isoimmunization complicated with severe hyperbilirubinemia and delayed profound anemia. Hyperbilirubinemia was controlled using intensive phototherapy. Although anemia was absent at birth, it appeared progressively with a nadir at 7.8 g/dL at 1-month postnatal age. Blood counts were monitored for 3 months but the patient did not require red blood cell transfusion. This report underlines the need for a prolonged and rigorous pediatric follow-up of children born in the context of maternofetal isoimmunization after the acute neonatal period. Furthermore, it stresses the necessity of DAT testing in all pregnant women, even those who are RH1-positive.

Management of red cell alloimmunized pregnancies using conventional methods compared with that of middle cerebral artery peak systolic velocity.

The aim of this retrospective study was to find out the effect of change in the management of red cell alloimmunized pregnancies from conventional method of amniocentesis to the Doppler assessment of middle cerebral artery peak systolic velocity (MCA-PSV). There were 29 alloimmunized pregnancies affected by red cell antibodies. Ten cases were managed by amniocentesis and another 19 were managed by MCA-PSV measurements. The antenatal management and perinatal outcome of both groups are presented. This study suggests that the non-invasive monitoring should be the method of choice to monitor alloimmunized pregnancies.

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.

Studies of the extraction of bilirubin from human amniotic fluid.

The recovery of unconjugated bilirubin from human amniotic fluid was studied using dichloromethane, chloroform/isopropanol (3:1 vol/vol), and chloroform/ methanol (3:1 vol/vol) extraction of human amniotic fluid that had been supplemented with bilirubin at various concentrations. Results were compared with those obtained with conventional chloroform extraction. Mean recoveries were found to be only 28% for chloroform and 25% for dichloromethane. When the polarity of chloroform was increased by the addition of an alcohol, the mean recovery increased to only 40% for chloroform/isopropanol and 38% for chloroform/ methanol. These results suggest that extraction methods for determination of amniotic fluid "delta OD(450)" (visible spectrophotometric absorbance [optical density] of bilirubin at 450 nm) tend to underestimate the result when compared with the nonextraction (direct-scan) method, on which the Liley Prognostication Chart is based. This finding should be clinically significant, particularly if extraction and direct-scan methods are used to monitor the condition of the same patient.

Infants with bilirubin levels of 30 mg/dL or more in a large managed care organization.

OBJECTIVE: To describe the incidence, etiology, treatment, and outcome of newborns with total serum bilirubin (TSB) levels >or=30 mg/dL (513 micro mol/L). DESIGN: Population-based case series. SETTING: Eleven Northern California Kaiser Permanente Medical Care Program hospitals and 1 affiliated hospital. PATIENTS: Eleven infants with TSB levels of >or=30 mg/dL in the first 30 days after birth, identified using computer databases from a cohort of 111,009 infants born 1995-1998. OUTCOME MEASURES: Clinical data from the birth hospitalization, rehospitalization, and outpatient visits in all infants; psychometric testing at age 5 (N = 3), neurologic examinations by child neurologists at age 5 (N = 3), or primary care providers (N = 7; mean age: 2.2 years); Parent Evaluation of Developmental Status (N = 8; mean age: 4.2 years). RESULTS: Maximum TSB levels of the 11 infants ranged from 30.7 to 45.5 mg/dL (525 micro mol/L to 778 micro mol/L; mean: 34.9 mg/dL [597 micro mol/L]). Four were born at 35 to 36 weeks gestation, and 7 were exclusively breastfed. Two had apparent isoimmunization; the etiology for the other 9 remained obscure, although only 4 were tested for glucose-6-phosphate dehydrogenase deficiency and 1 was bacteremic. None had acute neurologic symptoms. All received phototherapy and 5 received exchange transfusions. One infant died of sudden infant death syndrome; there was no kernicterus at autopsy. Two were lost to follow-up but were neurologically normal when last seen for checkups at 18 and 43 months. One child was receiving speech therapy at age 3. There were no significant parental concerns or abnormalities in the other children. CONCLUSIONS: In this setting, TSB levels >or=30 mg/dL were rare and generally unaccompanied by acute symptoms. Although we did not observe serious neurodevelopmental sequelae in this small sample, additional studies are required to quantify the known, significant risk of kernicterus in infants with very high TSB levels.

Evaluation and treatment of jaundice in the term newborn: a kinder, gentler approach.

Standard recommendations for evaluating and treating jaundice in term babies include following all babies closely for jaundice, obtaining several laboratory tests in those with early jaundice or bilirubin levels more than 12 to 13 mg/dL (205 to 222 mumol/L), using phototherapy to try to keep bilirubin levels below 20 mg/dL (342 mumol/L), and doing exchange transfusions if phototherapy fails, regardless of the cause of the jaundice. These recommendations are likely to lead to unnecessary testing and treatment of many jaundiced term infants. Because most jaundiced infants have no underlying illness, and the generally recommended laboratory tests lack sensitivity and specificity, they are seldom useful. In most babies, the only blood tests needed to evaluate jaundice are the blood type and group (of baby and mother) and a direct Coombs' test. A determination of direct bilirubin level should be added if jaundice is prolonged (greater than 2 to 4 weeks) or the baby has other signs of illness. Bilirubin toxicity is rare in term babies without hemolysis. In this low-risk group, the risks and cost of identifying and treating high bilirubin levels may exceed the benefits. Such infants need not be closely followed for jaundice. If significant jaundice is nonetheless found, treatment should be deferred to relatively high levels of serum bilirubin, with a goal of keeping bilirubin levels below 400 to 500 mumol/L (23.4 to 29.2 mg/dL). Babies with hemolytic disease should be followed more closely, and their bilirubin levels kept below 300 to 400 mumol/L (17.5 to 23.4 mg/dL). These recommendations should be reevaluated as new data become available. In the meantime, currently available data justify an approach to the jaundiced term infant that is less aggressive than previously recommended.

Protocolo de atencion de enfermeria en la prevencion primaria de la enfermedad hemolitica por incompatibilidad del factor RH en el recien nacido Hospital La Victoria de Bogota D.E / Nursing care protocol for primary prevention of haemolitic disease due to RH factor incompatibility in the newborn, Hospital La Victoria. Bogota D.E

La enfermedad hemolitica del recien nacido por incompatibilidad de Rh negativo es una de las patologias que afecta al neonato y que se ha venido estudiando desde 1939; esta incompatibilidad se refiere a la diferencia del Rh en una pareja donde la madre es Rh negativa y el padre Rh positivo. Cuando sangre Rh positiva se transfunde a una mujer Rh negativa, por error, o cuando pequenas cantidades (mas de un milimetro) de sangre fetal Rh positiva que contiene antigeno D heredado de un padre Rh positivo; entra en la circulacion materna durante el embarazo, o bien por aborto espontaneo, o inducido, o en el momento del parto, la madre no sensibilizada Rh negativa produce anticuerpos anti D. Una vez que ha ocurrido la isoinmunizacion, pequenas dosis de antigeno pueden estimular el incremento del titulo de anticuerpos, produciendo un aumento de la destruccion de los eritricitos y causando sintomatologia de enfermedad hemolitica, manifestaciones que pueden ir desde la simple evidencia de laboratorio con moderada hemolisis hasta anemia severa, acompanada de hepatoesplenomegalia como mecanismo compensador; al aumentar esta capacidad compensatorio por anemia profunda dara lugar a palidez, signos de descompensacion cardiaca, anasarca masiva y colapso cardiocirculatorio. Este cuadro clinico denominado hidropesia fetal da lugar frecuentemente a muerte intrauterina o inmediatamente despues de nacer. Generalmente al nacimiento no presenta ictericia, puesto que la placenta ha representado el papel de aclaramiento a la bilirrubina no conjugada..