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Objective: To evaluate which risk factors for RhD immunisation remain, despite adequate routine antenatal and postnatal RhIg prophylaxis (1000 IU RhIg) and additional administration of RhIg. The second objective was assessment of the current prevalence of RhD immunisations., Design: Prospective cohort study., Setting: The Netherlands., Population: Two-year nationwide cohort of alloimmunised RhD-negative women., Methods: RhD-negative women in their first RhD immunised pregnancy were included for risk factor analysis. We compared risk factors for RhD immunisation, occurring either in the previous non-immunised pregnancy or in the index pregnancy, with national population data derived from the Dutch perinatal registration (Perined)., Results: In the 2-year cohort, data from 193 women were eligible for analysis. Significant risk factors in women previously experiencing a pregnancy of an RhD-positive child (n = 113) were: caesarean section (CS) (OR 1.7, 95% CI 1.1-2.6), perinatal death (OR 3.5, 95% CI 1.1-10.9), gestational age >42 weeks (OR 6.1, 95% CI 2.2-16.6), postnatal bleeding (>1000 ml) (OR 2.0, 95% CI 1.1-3.6), manual removal of the placenta (MRP) (OR 4.3, 95% CI 2.0-9.3); these factors often occurred in combination. The miscarriage rate was significantly higher than in the Dutch population (35% versus 12.-5%, P < 0.001)., Conclusion: Complicated deliveries, including cases of major bleeding and surgical interventions (CS, MRP), must be recognised as a risk factor, requiring estimation of fetomaternal haemorrhage volume and adjustment of RhIg dosing. The higher miscarriage rate suggests that existing RhIg protocols need adjustment or better compliance., Tweetable Abstract: Complicated delivery (caesarean section, manual removal placenta, major bleeding) is the most valid risk factor for RhD immunization despite antenatal and postnatal RhIg., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Administration of RhD immunoglobulin (Ig) is important for RhD negative women throughout pregnancy and postnatally to prevent alloimmunisation and haemolytic disease of the fetus and newborn in subsequent pregnancies., Aims: The aim of this audit was to understand compliance with the Australian guidelines on RhD Ig prophylaxis in pregnancy., Materials and Methods: This was a retrospective audit of RhD negative pregnant women in Victoria, Northern Territory, Australian Capital Territory and Tasmania at maternity services of level 2 or higher care, between July 2017 and June 2018. Medical records were reviewed to identify how many RhD negative women received care compliant with the guidelines covering antibody testing, consent, administration of RhD Ig, and feto-maternal haemorrhage (FMH) quantification., Results and Conclusions: Analysis included 939 RhD negative women from 43 health services. Compliance with postnatal RhD Ig was high (98%); however, other practice was poor. Documented consent was obtained and recorded for 585 women (62%). Only 76% of eligible women received RhD Ig at the appropriate dose and time (28 and 34 weeks gestation). Similarly, management of potentially sensitising events was suboptimal with 78% receiving RhD Ig when recommended by guidelines. The results of our audit indicate a need for practice improvement across all aspects of care for women who need to receive RhD Ig. A major focus should be not just educating clinical staff, but also educating women to understand the importance of RhD Ig and the potential impact on subsequent pregnancies in order to improve guideline adherence and reduce risk., (© 2020 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Objective: To evaluate the cost-effectiveness of high-throughput, non-invasive prenatal testing (HT-NIPT) for fetal Rhesus D (RhD) genotype to guide antenatal prophylaxis with anti-D immunoglobulin compared with routine antenatal anti-D immunoglobulin prophylaxis (RAADP)., Design: Cost-effectiveness decision-analytic modelling., Setting: Primary care., Participants: A simulated population of 100 000 RhD-negative women not known to be sensitised to the RhD antigen., Methods: A decision tree model was used to characterise the antenatal care pathway in England and the long-term consequences of sensitisation events. The diagnostic accuracy of HT-NIPT was derived from a systematic review and bivariate meta-analysis; estimates of other inputs were derived from relevant literature sources and databases. Women in whom the HT-NIPT was positive or inconclusive continued to receive RAADP, whereas women with a negative result received none. Five alternative strategies in which the use of HT-NIPT may affect the existing postpartum care pathway were considered., Main Outcome Measures: Costs expressed in 2015GBP and impact on health outcomes expressed in terms of quality-adjusted life-years over a lifetime., Results: The results suggested that HT-NIPT appears cost saving but also less effective than current practice, irrespective of the postpartum strategy evaluated. A postpartum strategy in which inconclusive test results are distinguished from positive results performed best. HT-NIPT is only cost-effective when the overall test cost is £26.60 or less., Conclusions: HT-NIPT would reduce unnecessary treatment with routine anti-D immunoglobulin and is cost saving when compared with current practice. The extent of any savings and cost-effectiveness is sensitive to the overall test cost., Tweetable Abstract: HT-NIPT is cost saving compared with providing anti-D to all RhD-negative pregnant women., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Objective: To estimate the cost-effectiveness of first trimester non-invasive fetal RHD screening for targeted antenatal versus no routine antenatal anti-D prophylaxis (RAADP) or versus non-targeted RAADP., Design: Model based on a population-based cohort study., Setting: The Swedish health service., Population: Intervention subjects in the underlying cohort study were RhD-negative pregnant women receiving first trimester fetal RHD screening followed by targeted anti-D in 2010-2011 (n = 6723). Historical comparators were RhD-negative women who delivered in 2008-2009 when standard care did not include RAADP (n = 7099)., Methods: Healthcare costs for the three strategies were included for the first and subsequent pregnancies. For the comparison with non-targeted RAADP, the immunisation rate was based on the observed rate for targeted therapy and adjusted downwards by removing the influence of false negatives., Main Outcome Measure: Additional cost per RhD immunisation averted., Results: Compared with RAADP, targeted prophylaxis was associated with fewer immunisations (0.19 versus 0.46% per pregnancy) and lower costs (cost-savings of €32 per RhD-negative woman). The savings were from lower costs during pregnancy and delivery, and lower costs of future pregnancies through fewer immunisations. Non-targeted anti-D was estimated to result in 0.06% fewer immunisations and an additional €16 in cost-savings per mother, compared with targeted anti-D., Conclusion: Based on effect data from a population-based cohort study, targeted prophylaxis was associated with lower immunisation risk and costs versus no RAADP. Based on effect data from theoretical calculations, non-targeted RAADP was predicted to result in lower costs and immunisation risk compared with targeted prophylaxis., Tweetable Abstract: Fetal RHD screening and targeted prophylaxis resulted in lower immunisation risk and costs compared with no RAADP., (© 2015 Royal College of Obstetricians and Gynaecologists.)

Objective: To highlight the errors associated with the use of anti-D immunoglobulin in RhD antigen-negative women, and their resultant clinical impact during and after pregnancy, and to suggest strategies to reduce these errors., Design: Retrospective review of cumulative reporting to the UK confidential haemovigilance scheme, Serious Hazards of Transfusion (SHOT), between 1996 and 2011., Setting: Obstetric departments in the UK., Population: Mothers who require anti-D immunoglobulin to prevent RhD sensitisation during pregnancy or after birth., Methods: Hospital transfusion teams reported adverse events to the SHOT database., Main Outcome Measures: Reported number of events and their causes, and morbidity and mortality associated with errors., Results: In 15 years of reporting, SHOT haemovigilance has shown a total of 1211 errors related to the administration of anti-D immunoglobulin, particularly regarding omission or late administration (157/249 or 63% reported in 2011). Anti-D immunoglobulin errors comprised 13.7% (249/1815) of all SHOT reports in 2011. Failure to recognise women who already have RhD sensitisation occurred in 19 cases, and was followed by suboptimal monitoring of the pregnancy. Nine of the infants suffered haemolytic disease of the fetus and newborn (HDFN): one resulted in neonatal death and three required red cell transfusion., Conclusions: Babies as well as their mothers remain at risk from avoidable errors. More active attention at national and local levels to further education and training, particularly for midwives, is an absolute necessity. We recommend the use of a SHOT-devised anti-D administration flowchart, adapted locally into a checklist, to help reduce errors., (© 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.)

The prevention of Rhesus D alloimmunization through Rh immune globulin (RhIg) administration is the major indication for the accurate detection and quantification of fetomaternal hemorrhage (FMH). In the setting of D incompatibility, D-positive fetal cells can sensitize the D-negative mother, resulting in maternal anti-D alloantibody production. These anti-D alloantibodies may lead to undesirable sequelae such as hemolytic disease of the newborn (HDN). Since the widespread adoption of FMH screening and RhIg immunoprophylaxis, the overall risk of Rh alloimmunization and infant mortality from HDN has substantially decreased. The rosette screen, the initial test of choice, is highly sensitive in qualitatively detecting 10 mL of fetal whole blood in the maternal circulation. As the screen is reliant on the presence of the D antigen to distinguish fetal from maternal cells, it cannot be used to detect FMH in D-positive mothers or in D-negative mothers carrying a D-negative fetus. The Kleihauer-Betke acid-elution test, the most widely used confirmatory test for quantifying FMH, relies on the principle that fetal RBCs contain mostly fetal hemoglobin (HbF), which is resistant to acid-elution whereas adult hemoglobin is acid-sensitive. Although the Kleihauer-Betke test is inexpensive and requires no special equipment, it lacks standardization and precision, and may not be accurate in conditions with elevated F-cells. Anti-HbF flow cytometry is a promising alternative, although its use is limited by equipment and staffing costs. Hematology analyzers with flow cytometry capabilities may be adapted for fetal cell detection, thus giving clinical laboratories a potentially attractive automated alternative for quantifying FMH., (Copyright © 2011 Wiley Periodicals, Inc.)

Cyril Clarke was an outstanding general physician and lepidopterist. Late in his career, and stimulated by his work on the genetics of mimicry in butterflies, he became interested in the evolving field of medical genetics. His work on the relationship of blood groups to particular diseases led him and his team in Liverpool to evolve a remarkably successful approach to the prevention of Rhesus haemolytic disease of the newborn., (© 2012 Blackwell Publishing Ltd.)

Objective: To identify risk factors for Rhesus D (RhD) immunisation in pregnancy, despite adequate antenatal and postnatal anti-D prophylaxis in the previous pregnancy. To generate evidence for improved primary prevention by extra administration of anti-D Ig in the presence of a risk factor., Design: Case-control study., Setting: Nation-wide evaluation of the Dutch antenatal anti-D-prophylaxis programme., Cases: 42 RhD-immunised parae-1, recognised by first-trimester routine red cell antibody screening in their current pregnancy, who received antenatal and postnatal anti-D Ig prophylaxis (gifts of 1000 iu) in their first pregnancy., Controls: 339 parae-1 without red cell antibodies., Methods: Data were collected via obstetric care workers and/or personal interviews with women., Main Outcome Measure: Significant risk factors for RhD immunisation in multivariate analysis., Results: Independent risk factors were non-spontaneous delivery (assisted vaginal delivery or caesarean section) (OR 2.23; 95% CI:1.04-4.74), postmaturity (>or=42 weeks of completed gestation: OR 3.07; 95% CI:1.02-9.02), pregnancy-related red blood cell transfusion (OR 3.51; 95% CI:0.97-12.7 and age (OR 0.89/year; 95% CI:0.80-0.98). In 43% of cases, none of the categorical risk factors was present., Conclusions: In at least half of the failures of anti-D Ig prophylaxis, a condition related to increased fetomaternal haemorrhage (FMH) and/or insufficient anti-D Ig levels was observed. Hence, RhD immunisation may be further reduced by strict compliance to guidelines concerning determination of FMH and accordingly adjusted anti-D Ig prophylaxis, or by routine administration of extra anti-D Ig after a non-spontaneous delivery and/or a complicated or prolonged third stage of labour.

Background: The successful prevention of RhD disease has brought attention to other red blood cells' antigens causing alloimmunisation including RhC/c and RhE/e. Prenatal diagnosis of fetal Rh genotype from maternal blood is in clinical use in Europe but not in the USA., Objective: To estimate the collective reported diagnostic accuracy of fetal RhCE genotyping from peripheral maternal blood and compare the results of genotyping when fetal cells and free fetal DNA (FfDNA) are used., Search Strategy: English-written literature describing fetal RhCE determination from maternal blood using fetal cells or FfDNA was performed using medical subject headings and text words. The sources included Pubmed (1966-2007), Ovid (1966-2007), CINAHL, The Cochrane Library, ACP Journal Club and OCLC. Key words were prenatal diagnosis, fetal RhCE, fetal DNA in maternal blood and alloimmunisation., Selection Criteria: A study was considered eligible if it described fetal RhCE type determination using maternal peripheral blood reported in the English literature. Abstracts were excluded., Data Collection and Analysis: From each study, we determined the number of samples tested, fetal RhCE genotype, the source of the fetal DNA, gestational age, presence of alloimmunisation and confirmation of fetal RhCE type. Exclusions and inclusions were noted. We calculated composite estimates of accuracy using a weighted random effects model. We assessed the papers against an international quality, STARD checklist which is standards for reporting studies of diagnostic accuracy., Main Results: We identified 20 protocols in six English-written publications reporting fetal RhC/c (seven protocols) and/or E/e (13 protocols) genotyping using DNA obtained from maternal blood for a total of 369 samples. For RhC/c, 176 samples were tested and for RhE/e, 193 samples were tested. Accuracy was determined for each study and for all studies. The combined accuracy of fetal genotype was 96.3% for RhC/c and 98.2% for RhE/e. Only a few samples of the sorted cells were found to be a source for accurate diagnosis, but plasma was consistently the best source of fetal RhCE genotyping in 147/147 (100%) for RhC/c and 168/168 (100%) for RhE/e., Conclusions: The combined accuracy of noninvasive fetal RhC/c or RhE/e determination using maternal peripheral blood is 96.3% and 98.2%, respectively. FfDNA in maternal plasma is a better source for genotyping reported to be 100% correct for both RHCE genotypes. Further studies and reports of accuracy from laboratories performing the tests are required before prenatal determination of fetal RhC/c or RhE/e genotypes from maternal blood can safely replace the current methods used in the management of the RhC/c or RhE alloimmunised pregnancies.

Documented routine antenatal anti-D prophylaxis was given to 90% and 81-87% of eligible women at 28 and 34 weeks of gestation, respectively, during the early 1990s and early 2000s. With increasing experience and education, a significant improvement in the timing of the first (OR 0.26, 95% CI 0.16-0.41: P < 0.0001) and second injections (OR 0.40, 95% CI 0.26-0.61: P < 0.0001) occurred during the latter period. Despite these improvements, there was no reduction in the sensitisation rate at 0.4%. However, this low rate occurred despite significant proportions of women delivering more than 42 days after the second injection. Fifteen of the 16 sensitised women had received routine antenatal prophylaxis.

Objective: To observe the pharmacokinetics of intramuscular anti-D immunoglobulin (IgG) given for routine antenatal prophylaxis., Design: Prospective observational study., Setting: Maternity unit and antenatal serology laboratory in a district teaching hospital., Population: Forty-five rhesus-D-negative pregnant women not sensitised to RhD., Methods: Serial serum quantitations of anti-D IgG following the intramuscular injections of anti-D IgG 100 microg (500 IU) at 28 and 34 weeks of gestation. Anti-D IgG concentrations were assayed with the RFA-300 continuous flow analyser., Main Outcome Measures: The kinetic profile and duration of detectable anti-D IgG in maternal serum following the first and second injections of anti-D IgG., Results: For the 43 women in whom serial data were collected, there were no detectable differences between pregnancies with an RhD-positive (26) or -negative (17) fetus. Maximum IgG concentrations were detected two to five days following the first anti-D IgG injection and ranged between 0 and 28 ng/mL. Only 30% of women still undelivered at 40 weeks of gestation had detectable IgG at 2 ng/mL or greater. There was a significant relationship between higher maximum values and low maternal surface body area (R2 = 0.204, P = 0.002), but this did not influence duration of persistent IgG., Conclusion: Using previously published data, 70% women are not adequately protected with anti-D IgG 12 weeks after the first prophylactic injection. Despite this, previous clinical results suggest that the antenatal prophylaxis schedule used provides adequate protection and that the recommendation for the lowest concentration of protective anti-D IgG antibody levels currently in use is probably overestimated.

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%).

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.

Serology for the presence of anti-D after RhD-incompatible platelet transfusions was performed in 24 RhD-negative patients with haematological disease and 59 RhD-negative patients with non-haematological disease. None of the patients were given prophylaxis with anti-D to prevent RhD immunization. Eight out of 59 (13.5%) non-haematology patients developed detectable anti-D, whereas 0 out of 24 (0%) of the haematology patients formed anti-D (P = 0.06). The risk of alloimmunization after RhD-incompatible platelet transfusions using platelet concentrates prepared by modern technical methods appears to be small in patients with haematological disease, but is significant in non-immunocompromised patients.

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.

Alloimmunization to the D blood group antigen following the transfusion of D-positive red blood cells to a D-negative recipient may be prevented in most persons by a prompt and adequate dose of Rho (D) immune globulin (RhIG). Until recently, the only RhIG approved by the US Food and Drug Administration (FDA) for this indication required intramuscular injection, an inconvenient and painful route for the relatively large volume that may be required. We describe the successful prevention of Rh alloimmunization following the unintentional transfusion of D-positive red blood cells to a D-negative infant by the intravenous infusion of WinRho SD, a new RhIG that is FDA-approved for prevention of post-transfusion Rh alloimmunization by intravenous administration. We believe that this more convenient and less painful approach should be the treatment of choice for preventing Rh alloimmunization following the transfusion of D-positive red cells to a D-negative recipient.

The use of anti-D immunoglobulin has dramatically reduced the incidence of rhesus isoimmunization arising from pregnancy. A critical shortage of anti-D has developed and consumption must be reduced, preferably without increasing the risk of isoimmunization. The standard dosage of anti-D currently given at all gestational ages is 1 ampoule containing 125 micrograms of anti-D. Of the anti-D administered half is during the first trimester when a much lower dose could be used; 30 micrograms would remove from the maternal circulation the entire fetoplacental blood volume (3 ml) of a 12 week's pregnancy. A dose of 30 micrograms would also be adequate for most fetomaternal transfusions after 12 weeks but prior to the third trimester. A larger dose could be administered if maternal Kleihauer testing suggests the need for a supplementary dose. In the third trimester, the current regimen is appropriate - a dose of 125 micrograms of anti-D supplemented when needed on the basis of maternal Kleihauer testing. A lower dose ampoule of anti-D should be available. In addition, existing protocols for anti-D administration should be modified so that smaller more appropriate doses are given, better utilizing the limited supply of anti-D.