About diminished transport of maternal IgG (RhD alloimmunization) to the fetus.
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Female↗
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Antenatal genotyping of the blood groups of the fetus.
Antenatal genotyping of the fetus is now in widespread use as an aid to the clinical management in cases where there is the potential of haemolytic disease of the newborn occurring. The rapid diagnosis of an antigen-negative fetus will preclude the requirement for further, potentially risky invasive procedures being performed, whilst the determination of an antigen-positive fetus allows the potential of intensifying obstetric care for this pregnancy. Molecular genotyping is a major clinical application which has led from the determination of the molecular bases of blood group antigens expressed, most of which have been defined at the level of the gene. All assays used are dependent on the Polymerase Chain Reaction amplification of fetal DNA derived from either amniotic fluid or chorionic villi. Recent work has explored the potential of utilising fetal cells found to be present in maternal peripheral blood as a source of nucleic acid for prenatal diagnosis. Using non-invasive methods will preclude exposing mother and fetus to the potential hazards of invasive methods (amniocentesis, chorionic villus sampling and cordocentesis) which include miscarriage, fetal malformations and further maternal alloimmunisation.
Adult↗
A comparison of in vitro tests for predicting the severity of haemolytic disease of the fetus and newborn.
Haemolytic disease of the newborn (HDN) is characterized by the presence of IgG antibodies in the maternal circulation which cause haemolysis in the fetus by crossing the placenta and sensitizing red cells for destruction by macrophages in the fetal spleen. Numerous serological, quantitative and cellular assays have been developed to predict the severity of HDN. These assays all measure and/or characterize alloantibodies in the maternal circulation. Quantitative assays which accurately measure antibody levels correlate with disease severity better than serological assays which are inherently less precise. Nevertheless, high antibody levels are found in some cases of mild HDN and relatively low antibody levels are found in some severe cases. This suggests that disease severity is influenced by factors in addition to antibody concentration. These factors remain to be fully elucidated but may include the subclass and glycosylation of maternal antibodies, the structure, site density, maturational development and tissue distribution of blood group antigens, the efficiency of IgG transport to the fetus, the functional maturity of the fetal spleen, polymorphisms which affect Fc receptor function, and the presence of HLA-related inhibitory antibodies. Cellular assays which are sensitive to factors affecting antibody function have therefore been developed in an attempt to improve the prediction of disease severity. Although these assays are cumbersome, there are now sufficient data to suggest that some cellular assays, when used as part of a structured approach to diagnostic testing, may provide clinically-useful information to complement serological and quantitative assays.
Adult↗
RHD DNA screening for weak D, DEL and D+/- 'chimeras'.
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Blood Group Incompatibility↗
Antenatal fetal blood sampling for the management of alloimmunized pregnancies: effect upon maternal anti-D potency levels.
Increase in maternal anti-D concentrations after intrauterine investigation has been studied retrospectively in 95 rhesus (D) alloimmunized pregnancies; 48 were managed by fetal blood sampling (FBS) procedures (using fetoscopy or ultrasound-guided needle sampling) and 47 using amniocentesis. In those pregnancies where the fetus was rhesus (D) positive, the frequency of procedure-related increases (greater than 50%) in maternal anti-D potency was estimated following single procedures and found to be similar for the two methods of FBS employed (28%) and for amniocentesis (31%). The proportion of pregnancies showing an increase in anti-D potency was higher after ultrasound-guided needle sampling (75%) than after fetoscopic FBS (40%) and after amniocentesis (44%).
Amniocentesis↗
RhD genotyping by quantitative fluorescent polymerase chain reaction: a new approach.
OBJECTIVE: To develop a new method of RhD/d genotype determination using a quantitative fluorescent PCR (QF-PCR) assay. METHODS: Polymerase chain reaction amplification (PCR) of fragments of exon 7 of both the RHD and RHCE genes was performed from 32 amniotic fluid and 26 chorionic villus samples known to be heterozygous for the RHD gene, 74 peripheral blood samples of RhD-positive blood donors (homozygous or heterozygous) estimated by serologic typing and 24 RhD-negative fetal samples. The number of copies of the RHD gene in RhD-positive samples was determined by comparing the fluorescent intensities of the amplification products specific for the RHD and the RHCE genes. RESULTS: A ratio of fluorescent intensities of 1:1 clearly indicated D/D homozygous individuals whereas a ratio of 1:2 was demonstrated in samples from D/d heterozygous individuals. The mean fluorescent intensity ratio of the peak areas of homozygous samples was 1.12 (SD 0.128), the mean ratio of the peak areas of heterozygous samples was 0.51 (SD 0.060). Complete agreement was obtained between RhD/d typing by QF-PCR and RhD genotypes assessed by family studies and serological methods. CONCLUSIONS: The fluorescent PCR-based DNA test allows easy, rapid and accurate determination of the zygosity for the RHD gene. This new technique provides useful information for the clinical management of pregnancies of sensitised RhD-negative mothers.
Amniotic Fluid↗
Prenatal management of women who have partial Rh (D) antigen.
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Female↗
The economics of routine antenatal anti-D prophylaxis for pregnant women who are rhesus negative.
OBJECTIVE: To investigate the economics of routine antenatal anti-D prophylaxis in the prevention of haemolytic disease of the newborn, in support of the NICE appraisals process. DESIGN: Cost effectiveness analysis. SETTING: UK NHS. POPULATION/SAMPLE: Pregnant women who are RhD-negative. METHODS: A model was constructed to estimate the incremental cost effectiveness and cost utility of: (1) offering routine antenatal anti-D prophylaxis to all pregnant women who are RhD-negative; (2) offering routine antenatal anti-D prophylaxis to RhD-negative primigravidae, compared with conventional management alone. Effectiveness estimates were derived from a meta-analysis of two UK community-based studies. Costs were derived from published sources and NHS product lists. Threshold analysis was conducted to reflect the social value of routine antenatal anti-D prophylaxis through incorporating valuations of parental grief and fetal/neonatal loss. MAIN OUTCOME MEASURES: Cost per life year gained and cost per quality adjusted life year (QALY) gained. RESULTS: The cost per life year gained is in the range pound 5,000- pound 15,000. The inclusion of long term neurodevelopmental problems results in a cost utility ranging between pound 11,000 and pound 52,000 per QALY gained. Threshold analysis suggests that if fetal loss, parental grief and subsequent high intervention pregnancy are valued at greater than 9 QALYs, the comprehensive policy would be more attractive than the primigravidae policy, assuming a maximum acceptable threshold of pound 30,000 per QALY. CONCLUSION: Routine antenatal anti-D prophylaxis provides a cost effective intervention for preventing haemolytic disease of the newborn in the pregnancies of women who are RhD-negative.
Cost-Benefit Analysis↗
A review of the clinical effectiveness of routine antenatal anti-D prophylaxis for rhesus-negative women who are pregnant.
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Female↗
Red blood cell iso-immunisation in the Wellington area of New Zealand: the case for antenatal prophylaxis.
The present study aimed to calculate the rate of Rhesus D iso-immunisation during pregnancy in Wellington, New Zealand and to identify the timing of iso-immunisation. The notes of all women and their babies with positive antenatal anti-D antibody screens during the period 1994-2002 at the regional reference laboratory (Wellington Blood Transfusion Service) were reviewed to identify the antibody titre and the stage of pregnancy that the antibodies developed. Twelve percent of all tested pregnant women were Rhesus D negative and the annual immunisation rate during pregnancy was 1.4%. Sensitisation during the third trimester occurred in 50% of these women. Sensitisation in the third trimester was more common in primigravid women (87%) than in multiparous women (27%).
Erythrocytes↗
SUCCESSFUL PREVENTION OF EXPERIMENTAL RH SENSITIZATION IN MAN WITH AN ANTI-RH GAMMA2-GLOBULIN ANTIBODY PREPARATION: A PRELIMINARY REPORT.
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Antibodies↗
Molecular and serologic characterization of DWI, a novel "high-grade" partial D.
BACKGROUND: Accurate D antigen identification is essential for pretransfusion and prenatal evaluation to prevent anti-D alloimmunization. Quantitative and qualitative D variants may pose typing problems and require particular consideration because of differing potential for anti-D induction. STUDY DESIGN AND METHODS: A novel partial D, DWI, was discovered in an anti-D-alloimmunized D+ Austrian woman. This D variant was investigated by RHD genotyping and nucleotide sequencing, as well as characterization of its serologic properties. RESULTS: The proposita exhibited a single-nucleotide exchange in RHD Exon 7 (1073T>C) predicting a Met358Thr substitution in the sixth extracellular loop of the RhD polypeptide. All DWI individuals identified (the proposita and two relatives) were genotyped DWIdCcee, which, together with the family tree, was highly suggestive of a DWICe haplotype association. Epitope mapping studies revealed only minor D antigen modification with weakening but not loss of epitopes D1.1, D9.1, and D16.1. Antigen density varied individually between 8000 and 8600 D sites per erythrocyte. No known low-frequency Rh antigen was detected. Despite the highly retained D epitope composition, the DWI proposita's serum sample contained alloanti-D from an immunization event many years earlier. CONCLUSION: The findings of this investigation emphasize the possible clinical significance of "high-grade" partial D variants that are likely to be missed by routine serology.
Aged↗
RhD variants in Caucasians: consequences for checking clinically relevant alleles.
BACKGROUND: Weak D type carriers cannot be immunized against D except when antigen density is below 400 antigens per RBC, whereas partial D carriers can produce anti-D. STUDY DESIGN AND METHODS: A total of 168 blood samples from Caucasian individuals were studied because of weak D expression and/or anti-D production. Serologic analysis and molecular analysis were performed. RESULTS: In total, 70 partial D and 62 weak D were identified. Among weak D samples, 30 weak D Type 1 and 21 weak D Type 2 alleles were found. Five new alleles were characterized carrying 399G > T, 680T > C, 833G > A, 851C > T, and 1015G > A, respectively. According to previous studies, antigen density was up to 500 for weak D Type 1 and 2, except when there was a dCe haplotype in trans. Antigen density was below 400 antigens per red blood cell for the new variants and most other weak D variants. CONCLUSION: These results provide molecular characterization of five new D variants. They also suggest that it would be advantageous to develop in routine laboratories weak D Type 1 and 2 genotyping for serologically depressed D antigen. It will help to avoid wasting of D- red blood cell units because carriers may safely receive D+ units.
Alleles↗
Maternal ABO-mismatched blood for intrauterine transfusion of severe hemolytic disease of the newborn due to anti-Rh17.
BACKGROUND: Clinically significant antibodies to high-incident antigens present a challenge in hemolytic disease of the newborn. Antigen-negative blood may be difficult to obtain for intrauterine transfusion (IUT). In these instances, maternal blood is de facto compatible regardless of an ABO mismatch. CASE REPORT: A group B/D-- woman with a history of hemolytic disease of the newborn due to anti-Rh17 (titer 256) presented to the obstetrical clinic at 12 weeks gestation for management of her third pregnancy. She consented to donate blood for possible IUT. STUDY DESIGN AND METHODS: Washed maternal packed cells were suspended in saline to 75 percent Hct and irradiated before transfusion. The fetus was transfused via the intrahepatic vein. RESULTS: Ultrasound examination at 19 weeks indicated a hydropic fetus. The fetal blood group was O Rh+, direct antiglobulin test 4+, and hemoglobin 22 g per L. A total of 368 mL of maternal blood was transfused during seven procedures. Labor was induced at 38 weeks, and a 2560-g male infant was delivered by Caesarian-section due to fetal distress. The infant grouped as B Rh+, direct antiglobulin test negative. No group O red blood cells were detected. The hemoglobin level was 143 g per L rising to 209 g per L at discharge 3 days later. The indirect bilirubin was 55 micromol/L and remained stable during the hospital stay. Phototherapy was discontinued after 1 day, and the infant was discharged without an exchange or top-up transfusion. CONCLUSIONS: Maternal ABO-mismatched blood is an alternate source for IUT in instances when antigen-compatible allogenic blood is unavailable.
ABO Blood-Group System↗
Secondary anti-D immunization by Del red blood cells.
BACKGROUND: Recent molecular studies of the RHD gene have revealed that D(el) individuals retain a grossly intact RHD gene or have a portion of RHD in their genomes. No D(el) phenotype has yet been shown to induce a primary or secondary alloanti-D immunization, however. CASE REPORT: A 67-year-old D- Japanese woman with a history of allosensitization from transfusion of D+ red blood cells (RBCs) was negative for anti-D at admission. After she received RBCs from 19 apparently D- donors, she developed anti-D with an 8-fold titer. The titer of anti-D increased further to 128-fold after transfusions of cross-match-compatible D- negative RBCs from 40 donors over the next 2 years. Two of 59 donors were found to be RHD gene-positive and antigen D- with a D(el) phenotype, that is, RHD(K409K). CONCLUSION: This is the first case in which RBCs having the D(el) phenotype induced a secondary alloanti-D immunization. A D- donor with the RHD(K409K) allele was associated with the development of anti-D. Adverse episodes or evidence of hemolysis was not observed after the transfusion of RHD(K409K) RBCs. Further clinical evidence is needed to reveal whether the D(el) phenotype has a clinically relevant potential for anti-D immunization.
Aged↗
Novel weak D types 31 and 32: adsorption-elution-supported D antigen analysis and comparison to prevalent weak D types.
BACKGROUND: Weak D types are thought to express rather quantitative than qualitative D antigen variants. Distinct type-specific phenotypes and weak D cases with anti-D alloimmunization, however, suggest a variable degree of D antigen alteration. STUDY DESIGN AND METHODS: Variant D types were investigated by use of molecular typing, RHD sequencing, extended serologic D antigen investigations, and flow cytometric D antigen density determination. RESULTS: Two novel weak D types were discovered, termed weak D type 31 and 32 with single RHD nucleotide substitutions coding for amino acid exchanges in predicted intracellular RhD polypeptide stretches, with antigen densities of approximately 130 and 50 D sites per red blood cell, respectively. Adsorption-elution technique-supported D epitope mapping of these two weak D types, the recently described weak D type 26, and of the most common Central European weak D types (weak D types 1, 2, 3, 4.0, and 4.1) demonstrated the expression of all tested D epitopes. In contrast, a distinct D epitope loss was detected in weak D type 15 and partial D control samples. CONCLUSION: All novel and prevalent weak D types expressed all tested D epitopes. Our results indicate that adsorption-elution techniques may be of advantage whenever D epitope loss is suspected in extremely weak D variants.
Adult↗
A comprehensive analysis of DEL types: partial DEL individuals are prone to anti-D alloimmunization.
BACKGROUND: The D antigen of the polymorphic Rh blood group system is of particular clinical importance regarding transfusion- and pregnancy-induced alloimmunization. Different RhD variants with specific clinical implications have been characterized. The least expressed D variants collectively called DEL are serologically detectable only by adsorption-elution techniques, with so far only poorly defined antigenic properties. STUDY DESIGN AND METHODS: A comprehensive immunohematologic analysis of five of the six currently known DEL genotypes was performed. DEL phenotypes associated with the RHD(M295I), RHD(IVS3+1g>a), RHD(K409K), RHD(X418L), or RHD(IVS5-38del4) allele were characterized with extended serology and flow cytometry. RESULTS: Epitope mapping with adsorption-elution revealed a prominent D epitope loss in the RHD(IVS3+1g>a)-associated DEL phenotype, whereas in the other four DEL types no signs of qualitative D antigen alteration were detected. The observation of alloanti-D in two RHD(IVS3+1g>a) cases confirmed the partial nature of this DEL phenotype. The RHD(M295I) phenotype exhibited the highest D antigen expression among all investigated DEL types, as determined by a semiquantitative adsorption-elution approach and flow cytometry. CONCLUSION: In conclusion, evidence is provided that different DEL genotypes code either for partial or complete D antigen expression and that this finding is clinically relevant.
Adult↗
Partial D, weak D types, and novel RHD alleles among 33,864 multiethnic patients: implications for anti-D alloimmunization and prevention.
BACKGROUND: The D antigen includes category D, partial D, and weak D types, which are important because anti-D alloimmunization can occur in some but not all persons that express a variant RHD allele. At present, there is little prospective information on the prevalence of D variants among obstetric patients and potential transfusion recipients. STUDY DESIGN AND METHODS: The RHD alleles were prospectively examined in a large patient population identified on the basis of a difference in anti-D reactivity between two reagents. RESULTS: Fifty-five discrepancies (0.96% of D-) were noted among 33,864 ethnically diverse patients over 18 months, of which 54 represented mutated RHD alleles. Seven obstetric patients were assigned D- status based on serology; only 1 patient had a partial RHD allele. Ten of 25 (36%) obstetric patients and 4 of 6 (67%) female potential transfusion recipients of childbearing age or younger were assigned D+ status, and they expressed a D variant known to permit anti-D alloimmunization. In total 20 RHD alleles were identified including category, DVa or DVa-like alleles (n = 7), DAR (n = 8), and four novel RHD alleles including two new DAU alleles. CONCLUSION: Given the complexity of D antigen expression, it is concluded that some clinically important D variants identified by standard serologic analysis phenotype as D+ and are potentially at risk for the development of anti-D.
Adult↗