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PubMed2003

Prevention of Rh alloimmunization.

OBJECTIVE: To provide guidelines on use of anti-D prophylaxis to optimize prevention of rhesus (Rh) alloimmunization in Canadian women. OUTCOMES: Decreased incidence of Rh alloimmunization and minimized practice variation with regards to immunoprophylaxis strategies. EVIDENCE: The Cochrane Library and MEDLINE were searched for English-language articles from 1968 to 2001, relating to the prevention of Rh alloimmunization. Search terms included: Rho(D) immune globulin, Rh iso- or allo-immunization, anti-D, anti-Rh, WinRho, Rhogam, and pregnancy. Additional publications were identified from the bibliographies of these articles. All study types were reviewed. Randomized controlled trials were considered evidence of highest quality, followed by cohort studies. Key individual studies on which the principal recommendations are based are referenced. Supporting data for each recommendation is briefly summarized with evaluative comments and referenced. VALUES: The evidence collected was reviewed by the Maternal-Fetal Medicine and Genetics Committees of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the Evaluation of Evidence guidelines developed by the Canadian Task Force on the Periodic Health Exam. RECOMMENDATIONS: 1. Anti-D Ig 300 microg IM or IV should be given within 72 hours of delivery to a postpartum nonsensitized Rh-negative woman delivering an Rh-positive infant. Additional anti-D Ig may be required for fetomaternal hemorrhage (FMH) greater than 15 mL of fetal red blood cells (about 30 mL of fetal blood). Alternatively, anti-D Ig 120 microg IM or IV may be given within 72 hours of delivery, with testing and additional anti-D Ig given for FMH over 6 mL of fetal red blood cells (12 mL fetal blood). (I-A) 2. If anti-D is not given within 72 hours of delivery or other potentially sensitizing event, anti-D should be given as soon as the need is recognized, for up to 28 days after delivery or other potentially sensitizing event. (III-B) 3. There is poor evidence regarding inclusion or exclusion of routine testing for postpartum FMH, as the cost-benefit of such testing in Rh mothers at risk has not been determined. (III-C) 4. Anti-D Ig 300 microg should be given routinely to all Rh-negative nonsensitized women at 28 weeks' gestation when fetal blood type is unknown or known to be Rh-positive. Alternatively, 2 doses of 100-120 microg may be given (120 microg being the lowest currently available dose in Canada): one at 28 weeks and one at 34 weeks. (I-A) 5. All pregnant women (D-negative or D-positive) should be typed and screened for alloantibodies with an indirect antiglobulin test at the first prenatal visit and again at 28 weeks. (III-C) 6. When paternity is certain, Rh testing of the baby's father may be offered to all Rh-negative pregnant women to eliminate unnecessary blood product administration. (III-C) 7. A woman with "weak D" (also known as Du-positive) should not receive anti-D. (III-D) 8. A repeat antepartum dose of Rh immune globulin is generally not required at 40 weeks, provided that the antepartum injection was given no earlier than 28 weeks' gestation. (III-C) 9. After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, nonsensitized D-negative women should be given a minimum anti-D of 120 microg. After 12 weeks' gestation, they should be given 300 microg. (II-3B) 10. At abortion, blood type and antibody screen should be done unless results of blood type and antibody screen during the pregnancy are available, in which case antibody screening need not be repeated. (III-B) 11. Anti-D should be given to nonsensitized D-negative women following ectopic pregnancy. A minimum of 120 microg should be given before 12 weeks' gestation and 300 microg after 12 weeks' gestation. (III-B) 12. Anti-D should be given to nonsensitized D-negative women following molar pregnancy because of the possibility of partial mole. Anti-D may be withheld if the diagnosis of complete mole is certain. (III-B) 13. At amniocentesis, anti-D 300 microg should be given to nonsensitized D-negativeesis, anti-D 300 microg should be given to nonsensitized D-negative women. (II-3B) 14. Anti-D should be given to nonsensitized D-negative women following chorionic villous sampling, at a minimum dose of 120 microg during the first 12 weeks' gestation, and at a dose of 300 microg after 12 weeks' gestation. (II-B) 15. Following cordocentesis, anti-D Ig 300 microg should be given to nonsensitized D-negative women. (II-3B) 16. Quantitative testing for FMH may be considered following events potentially associated with placental trauma and disruption of the fetomaternal interface (e.g., placental abruption, blunt trauma to the abdomen, cordocentesis, placenta previa with bleeding). There is a substantial risk of FMH over 30 mL with such events, especially with blunt trauma to the abdomen. (III-B) 17. Anti-D 120 microg or 300 microg is recommended in association with testing to quantitate FMH following conditions potentially associated with placental trauma and disruption of the fetomaternal interface (e.g., placental abruption, external cephalic version, blunt trauma to the abdomen, placenta previa with bleeding). If FMH is in excess of the amount covered by the dose given (6 mL or 15 mL fetal RBC), 10 microg additional anti-D should be given for every additional 0.5 mL fetal red blood cells. There is a risk of excess FMH, especially when there has been blunt trauma to the abdomen. (III-B) 18. Verbal or written informed consent must be obtained prior to administration of the blood product Rh immune globulin. (III-C) VALIDATION: These guidelines have been reviewed by the Maternal-Fetal Medicine Committee and the Genetics Committee, with input from the Rh Program of Nova Scotia. Final approval has been given by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada.

Canada↗
PubMed2002

Ultrasonographic monitoring of pregnancies complicated by red blood cell alloimmunization in a cohort with mild to moderate risk according to previous obstetric outcome.

AIM: To evaluate the detection rate of fetal anemia and pregnancy outcome as related to our policy of monitoring pregnancies with red blood cell alloimmunization. METHODS: From August 1997 to July 2000 35 pregnant women with maternal red blood cell alloantibodies were monitored by ultrasonographic measurements of the fetal spleen perimeter and peak systolic Doppler flow velocities of the middle cerebral artery, by semiquantification of maternal antibody titers and by general ultrasonographic and clinical evaluation. According to previous obstetric outcome they all had mild to moderate risk of developing fetal anemia. RESULTS: Eleven fetuses were anemic defined as a hemoglobin value < or = 2SD according to gestational age. A spleen perimeter > + 2SD and a middle cerebral artery peak systolic velocity > 95% prediction interval showed sensitivity and specificity of 64 and 92% and 45 and 100%, respectively. The area under receiver operating characteristic curves was 0.926 (95% CI 0.842-1.000; P < 0.001) for the spleen perimeter and 0.837 (95% CI 0.688-0.987; P < 0.01) for the middle cerebral artery peak systolic velocity. Cordocentesis was performed in one pregnancy only. None of the fetuses developed hydrops and all infants survived. Twelve women delivered before 37 weeks gestation. In 10 patients cesarean section was performed due to possible fetal anemia. Six of the 10 neonates had normal hemoglobin values. CONCLUSIONS: The ultrasonographic parameters did not predict all cases of fetal anemia defined as a hemoglobin concentration < or = 2SD according to gestational age. The present policy of monitoring seemed to reduce the number of invasive tests but possibly increased the number of preterm and cesarean deliveries.

Adult↗
PubMed2004

RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order.

Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal-fetal genotype incompatibility (MFG) test used in an earlier case-parent trio study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case-parent trios to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the second- and later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects.

Birth Order↗
PubMed1997

Specificity and sensitivity of RHD genotyping methods by PCR-based DNA amplification.

We have compared the sensitivity and specificity of four PCR methods of RHD gene detection using different sets of primers located in the regions of highest divergence between the RHD and RHCE genes, notably exon 10 (method I), exon 7 (method II), exon 4 (method III) and intron 4 (method IV). Methods I-III were the most sensitive and gave a detectable signal with D-pos/D-neg mixtures containing only 0.001% D-positive cells. Moreover, method II could detect the equivalent DNA amount present in only three nucleated cells in the assay without hybridization of PCR products, whereas the sensitivity of the other methods was 10-50 times less. Investigation of D variants indicated that false-negative results were obtained with method II (D(IVb) variant), method III (D(VI) and DFR variants) and method IV (D(VI) variants), but not method I. Weak D (D(u)) was correctly detected as D-positive by all methods, but most cases of Rh(null) appeared as false-positives, as they carry normal RH genes that are not phenotypically expressed. Some false-positive results were obtained with method I in a few Caucasian DNA samples serotyped as RhD-neg but carrying a C- or E-allele, whereas a high incidence of false-positives was found among non-Caucasian Rh-negative samples by all methods. In the Caucasian population, however, we found a full correlation between the predicted genotype and observed phenotype at birth of 92 infants. Although we routinely use the four methods for RHD genotyping, a PCR strategy based on at least two methods is recommended.

Blotting, Southern↗
PubMed1999

Detection of weak D and D(VI) red cells in D-negative mixtures by flow cytometry: implications for feto-maternal haemorrhage quantification and D typing policies for newborns.

Quantitation of feto-maternal haemorrhage (FMH) by flow cytometry (FC) has been shown to be more accurate than the Kleihauer-Bekte test. Fetal cells will be predominately of R1r or R2r phenotype, with antigen site numbers per cell (SPC) of between 9900 and 16000. If the fetus is of weak D or partial D(VI) phenotype, fewer SPC will be present. Red cells from 20 adult weak D samples were mixed with rr red cells to give 1% mixes. Mixtures were stained and analysed by FC, using two different monoclonal reagents. The SPC of each sample was measured using SOL-ELSA with Scatchard plot analysis. 18 samples could not be distinguished and had <1000 SPC. Two samples that could be distinguished had 1350 and 3000 SPC. Red cells from seven samples of D(VI) were also analysed. None of these samples could be distinguished: SPC were all <1000. Although one of the reagents used reacts with D(VI) cells, quantitation of a D(VI) FMH would not be possible due to low SPC. The ability of fetal red cells with low Rh D SPC to cause immunization is questionable; failure to measure FMH in these cases is unlikely to cause clinical problems, as long as suitably sensitive serological reagents and techniques are used to type all weak D and D variant babies as Rh D positive, and thus ensure that the mother is given the appropriate dose of anti-D.

Adult↗
PubMed2000

CHO expression of a novel human recombinant IgG1 anti-RhD antibody isolated by phage display.

Replacement of the hyperimmune anti-Rhesus (Rh) D immunoglobulin, currently used to prevent haemolytic disease of the newborn, by fully recombinant human anti-RhD antibodies would solve the current logistic problems associated with supply and demand. The combination of phage display repertoire cloning with precise selection procedures enables isolation of specific genes that can then be inserted into mammalian expression systems allowing production of large quantities of recombinant human proteins. With the aim of selecting high-affinity anti-RhD antibodies, two human Fab libraries were constructed from a hyperimmune donor. Use of a new phage panning procedure involving bromelin-treated red blood cells enabled the isolation of two high-affinity Fab-expressing phage clones. LD-6-3 and LD-6-33, specific for RhD. These showed a novel reaction pattern by recognizing the D variants D(III), D(IVa), D(IVb), D(Va), D(VI) types I and II. D(VII), Rh33 and DFR. Full-length immunoglobulin molecules were constructed by cloning the variable regions into expression vectors containing genomic DNA encoding the immunoglobulin constant regions. We describe the first, stable, suspension growth-adapted Chinese hamster ovary (CHO) cell line producing a high affinity recombinant human IgG1 anti-RhD antibody adapted to pilot-scale production. Evaluation of the Fc region of this recombinant antibody by either chemiluminescence or antibody-dependent cell cytotoxicity (ADCC) assays demonstrated macrophage activation and lysis of red blood cells by human lymphocytes. A consistent source of recombinant human anti-RhD immunoglobulin produced by CHO cells is expected to meet the stringent safety and regulatory requirements for prophylactic application.

Animals↗
PubMed2002

Fetal RHD genotyping in maternal serum during the first trimester of pregnancy.

Fetal RHD genotype determination is useful in the management of sensitized RhD-negative pregnant women. It can be ascertained early during pregnancy by chorionic villus sampling (CVS) or amniocentesis. However, these procedures are invasive, resulting both in an increased risk of fetal loss and in an increased severity of immunization due to fetomaternal haemorrhage. A reliable determination of RHD genotype by fetal DNA analysis in maternal serum during the first trimester of pregnancy is reported in this study. One hundred and six sera from RhD-negative pregnant women were obtained during the first trimester of pregnancy. These sera were tested for the presence of RHD gene using a new real-time polymerase chain reaction assay and the results compared with those obtained later in pregnancy on amniotic fluid cells and by RHD serology of the new-born. All sera from women carrying a RhD-positive fetus (n = 62) gave positive results for RHD gene detection and sera from women carrying a RhD-negative fetus (n = 40) were negative. The high level of accuracy of fetal RHD genotyping obtained in this study could enable this technique to be offered on a routine basis for the management of RhD-negative patients during the first trimester of pregnancy.

Amniocentesis↗
PubMed2003

Clearance of red cells by monoclonal IgG3 anti-D in vivo is affected by the VF polymorphism of Fcgamma RIIIa (CD16).

Human red cells (RBC) coated with IgG anti-D are cleared from the circulation to the spleen by macrophages which express IgG receptors (Fcgamma R). Polymorphisms of Fcgamma RIIa and Fcgamma RIIIa affect IgG binding in vitro, and may alter the efficiency of clearance of immune complexes in vivo. In a RBC clearance study, 22 Rh D-negative subjects were given 100-400 micro g human monoclonal or polyclonal IgG anti-D i.m. followed 48 h later by 51Cr-labelled D+ RBC. The half lives of the infused D+ RBC were determined, together with the coating levels of anti-D on the D+ RBC. Fcgamma RIIA and FcgammaRIIIA genotyping was performed. Large ranges of phagocytosis and extracellular lysis of RBC in vitro, and of half lives of RBC in vivo, were observed. Clearance of RBC coated with monoclonal IgG3 anti-D (BRAD-3) was more rapid in five subjects homozygous for Fcgamma RIIIa-F/F158 than in three subjects expressing the Fcgamma RIIIa-V158 allele (P = 0.024). This effect was not observed, however, for those individuals given polyclonal anti-D. There was also no significant difference in the efficiency of RBC destruction in vitro or of RBC clearance in vivo between the subjects analysed for individual genotypes or alleles or combinations of alleles. In conclusion, the presence of the Fcgamma RIIIa-V158 allele compromised the efficiency of removal of RBC coated with IgG3 anti-D.

Antibodies, Monoclonal↗
PubMed2000

Detection of massive transplacental haemorrhage by flow cytometry.

Flow cytometry has been shown to be a more accurate and sensitive method than the Kleihauer-Betke test for the measurement of feto-maternal haemorrhage in Rh(D) incompatibility. This report describes the successful use of flow cytometry to detect and monitor the management of a massive transplacental haemorrhage (105 ml) of fetal Rh(D) positive cells in a Rh(D) negative woman. The report highlights the accuracy and reproducibility of the test and the stability of a blood sample when transferred 596 kilometres to a central testing facility.

Adolescent↗
PubMed1997

A quality assurance scheme for the Kleihauer test: the Scottish experience 1988-1996.

This report describes the experience gained in the last 8 years of implementing and administering a Quality Assurance Scheme dedicated to improving the reliability of Kleihauer test results in Scotland. Initially the five transfusion centres in Scotland were the only participants, but since 1992 all 15 hospital laboratories in Scotland performing the Kleihauer test to ensure an adequate dose of anti-D is administered to Rh-negative women, at risk of developing allo anti-D, have joined this voluntary scheme. As a result of the standardization of technical methods, improvement in reporting of QA results has been observed since 1994.

Feedback↗
PubMed2001

The frequency of anti-C + anti-G in the absence of anti-D in alloimmunized pregnancies.

Anti-D+C are often initially identified in sera from alloimmunized women. Anti-G may be present in these samples, mimicking anti-D+C, and therefore the differentiation of anti-D, -C and -G may be important. Sera from 27 alloimmunized women, initially identified as containing anti-D + anti-C, were analysed by adsorption/elution studies in the presence of polyethylene glycol (PEG) using R(0)r (D+C-G+) and r'r(D-C+G+) red blood cells (RBC). Additionally, 15/27 samples were tested by adsorption in the presence of PEG and subsequently warm elution, using rGr (D-C-G+) RBC. Anti-G + anti-C, without anti-D, were identified in 4/27 samples (14.8%) and none of the newborn children needed postpartum treatment. The combination of D+G, D+C and D+C+G antibodies occurred in 25.9%, 11.1% and 48.1% of the women, respectively. Overall, anti-G was detected in 24/27 samples (88.9%). Pregnant women shown to have anti-G+C but not anti-D should receive Rh immune globulin. Additionally, the finding of apparent anti-D+C during pregnancy in D-negative spouses may lead to paternity testing and therefore a correct antibody identification is necessary.

ABO Blood-Group System↗
PubMed2001

An anti-idiotopic antibody-based enzyme-linked immunosorbent assay for the quantification of the monoclonal anti-D BRAD-5.

OBJECTIVES: We aimed to develop an anti-idiotopic antibody-based enzyme-linked immunosorbent assay (ELISA) to quantify human monoclonal anti-D using BRAD-5 as a model system. MATERIALS AND METHODS: One of the anti-idiotopic antibodies 2E6 was used to capture BRAD-5 with the other anti-idiotopic antibody 3B1 biotinylated for detection. RESULTS: The assay developed can detect BRAD-5 at < 2 ng/ml. Assay interference caused by heterophilic antibodies in some human sera was removed by preincubation with bovine serum. The assay is reproducible with intra- and inter-assay coefficient of variation (CV) < 10%. CONCLUSION: This ELISA should prove of benefit in developing a monoclonal anti-D for prophylactic use.

Animals↗
PubMed2001

Paediatric transfusion.

Paediatric transfusion encompasses a wide range of clinical circumstances including the consideration of maternal antibodies, the changing nature of the transfusion recipient with respect to growth and development, and the management of inherited conditions which if optimally treated in early life may have problems which are delayed or less severe in adult life. Whilst the transfusion of adults and children has much in common, a child cannot be considered as a scaled down adult; there are many important differences. Developmental changes are most marked in the neonate and, together with the fact that their antibodies are maternally derived, this population provide some of the most striking challenges. The increased use of intra uterine transfusion adds an extra dimension here. A particular paediatric concern is the long-term consequences of transfusion. It is to be hoped that paediatric transfusion recipients will live long enough that any potential problems will manifest themselves, thus the aim must be to minimize transfusion risks.

Blood Cells↗
PubMed2002

Alloimmunization to RhD antigen in RhD-incompatible haemopoietic cell transplants with non-myeloablative conditioning.

BACKGROUND AND OBJECTIVES: Following exposure to RhD antigen, anti-D develops in up to 20% of RhD-negative patients on chemotherapy, but seldom in the recipients of haemopoietic cell (HC) or solid-organ transplants. Data on anti-D formation come from HC transplants using myeloablative conditioning; no data are available for the non-myeloablative HC transplants. The two types of transplant have a distinct isohaemagglutinin disappearance rate and different kinetics of post-transplant red-cell engraftment. The objective of the study was to analyse anti-D formation in patients receiving non-myeloablative transplants from RhD-incompatible donors. MATERIALS AND METHODS: Sixteen patients were analysed: nine RhD-negative recipients of RhD-positive haemopoietic cells; and seven RhD-positive recipients of a graft from a RhD-negative donor. Patients were sequentially tested for irregular antibodies, as well as donor/recipient chimerism by cytogenetics and analysis of DNA variable-number tandem repeats. RESULTS: Despite having received 7-499 ml of D-positive red cells, none of the RhD-negative recipients developed anti-D. The median follow-up was 202 days. By contrast, anti-D was identified in one of seven RhD-positive recipients of an RhD-negative graft. CONCLUSIONS: Non-myeloablative conditioning containing fludarabine and/or Campath 1H, with cyclosporin A given post-transplant, effectively prevents anti-D formation in RhD-negative recipients of a RhD-positive graft. However, anti-D developed in an RhD-positive recipient of an RhD-negative graft, who was also exposed to RhD-positive blood products before and after the transplant. Transfusion of RhD-positive products should be avoided in such patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Diagnosis of fetal anemia with Doppler ultrasound in the pregnancy complicated by maternal blood group immunization.

We investigated whether Doppler measurement of the fetal middle cerebral artery peak systolic velocity can be used to detect fetal anemia in pregnancies complicated by maternal blood group immunization. We first studied normal values for the middle cerebral artery peak systolic velocity in 135 fetuses (Group A), and also in 23 fetuses at risk for anemia who underwent 56 cordocenteses to assess the fetal hematocrit (Group B). A test to detect fetal anemia, based on the middle cerebral artery peak systolic velocity, was developed by using the data of the fetuses of Group A and Group B. Successively, the middle cerebral artery peak systolic velocity was prospectively determined in 16 fetuses at risk for anemia who underwent 42 cordocenteses (Group C) to assess the test developed, in a multicenter prospective fashion, by using the data of Group A and Group B. In the normal fetuses an exponential model expressed the increase of the middle cerebral artery peak systolic velocity values with advancing gestation. By using the data of the fetuses of Group A and Group B, four zones of anemia risk were identified. In Group C, none of the anemic fetuses had the middle cerebral artery peak velocity below the normal mean value, whereas all of the anemic fetuses had the peak velocity above the normal mean. The middle cerebral artery blood velocity increases with advancing gestation and is a non-invasive method of detecting anemia in pregnancies complicated by maternal blood group immunization.

Adult↗
PubMed1998

Prospective non-invasive monitoring of pregnancies complicated by red cell alloimmunization.

Our purpose was to evaluate the impact of non-invasive assessment of fetal anemia and anti-D antibody quantification on the timing and frequency of invasive procedures in pregnancies complicated by rhesus alloimmunization. Nineteen consecutive non-hydropic pregnancies referred to the fetal medicine center were assigned a prior risk category (none/mild, moderate or severe) and monitored by: (1) serial fetal measurements of umbilical vein maximal flow velocity (UVVmax), liver length and spleen perimeter measurements; and (2) serial anti-D antibody concentration. Invasive tests for fetal anemia (amniocentesis or fetal blood sampling) were deferred in the absence of abnormal ultrasound findings and/or rising antibody levels. In six cases serial non-invasive tests were normal with stable antibody levels, and no invasive tests were performed; four infants were mildly affected, one was unaffected and one required postnatal exchange transfusion. In the remaining 13 affected cases, amniocentesis was performed in nine cases for: elevated UVVmax alone (n = 3), elevated UVVmax and an increased antibody level (n = 2), or normal UVVmax with an increased antibody level (> 15 IU/ml) and severe prior risk category (n = 4). Six fetuses underwent fetal blood sampling (initial hematocrit 9-29%), and five of these had an elevated UVVmax. Liver length and spleen perimeter measurements were increased in only one anemic fetus (hematocrit 13%). Of 17 infants born alive, an elevated UVVmax prior to delivery was predictive of the need for exchange transfusion (six of seven cases with an elevated UVVmax vs. one of ten with a normal UVVmax; chi 2 = 5.73, p = 0.017 with Yates' correction). These preliminary data suggest that pregnancies with a mild or no history of fetal anemia may be monitored by a combination of serial antibody quantification and Doppler monitoring of UVVmax.

Adult↗