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Objectives: To examine local patient safety events related to the administration of anti-Rh(D) immune globin (RhIG) during pregnancy, and to follow-up with targeted educational intervention to improve knowledge of this process., Background: Administration RhIG is established treatment for the prevention of haemolytic disease of the foetus and newborn (HDFN). However, patient safety events in relation to its correct use continue to occur., Methods: A retrospective audit of patient safety events related to RhIG administration during pregnancy was performed. Targeted educational intervention in the form of PowerPoint® presentation were given to nursing staff, laboratory staff and physicians and evaluated with pre- and post-tests using multiple-choice questions given immediately before and after the presentation., Results: An annual incidence of 0.24% of patient safety events related to the administration of RhIG during pregnancy was found. These events were mostly in the preanalytical phase, for example mislabelled samples or samples for D-rosette/Kleihauer-Betke testing drawn from the baby, not the mother. Using Bayesian analysis, the probability of positive effect for the targeted educational intervention was 100% with a median improved score of 29%. This was compared with a control group using standard curriculum education intervention based on the current curriculum for nursing, laboratory and medical students which showed a median improved score of only 4.4%., Conclusions: Administration of RhIG during pregnancy is a multistep process involving health care professionals of several disciplines providing opportunities to enhance the curriculum for nursing, laboratory and medical students and to ensure on-going education., (© 2023 The Authors. Transfusion Medicine published by John Wiley & Sons Ltd on behalf of British Blood Transfusion Society.)

Objectives: To reduce the risk of RhD alloimmunization during the last trimester of pregnancy, a targeted routine antenatal anti-D prophylaxis (RAADP) programme was implemented in Norway in 2016. Here, we present and discuss our experience with the nationwide implementation of the programme, and report sample uptake and preliminary data of de novo anti-D in pregnancy., Background: The targeted RAADP was advised by the academic community and evaluated by the health authorities. A National Working Group has conducted the implementation in the transfusion services and contributed to organise the administration of the antenatal anti-D prophylaxis. Fetal RhD type is determined by non-invasive prenatal testing at gestational week 24, and anti-D prophylaxis is administrated at gestational week 28 only to women with RhD positive fetuses., Methods: We describe the implementation process of targeted RAADP in Norway. The sample uptake is calculated by comparing the number of fetal RHD screens with the expected number of samples., Results: The sample uptake shows regional variations: 88%-100% after 3 years. Promising decrease in de novo anti-D detected during pregnancy is observed., Conclusions: Nationwide targeted RAADP is implemented and included in the Norwegian maternity care programme. Compliance to sample uptake should further improve in some regions. A remaining issue to fulfil is the documentation of the accuracy of the fetal RHD-typing at all sites. Post-natal prophylaxis will then be guided by the fetal RHD result. Dedicated registries will ensure data to evaluate the expected reduction in pregnancy-related RhD immunisations, which is the final success criterion of the programme., (© 2021 British Blood Transfusion Society.)

Aim: To determine the impact of Rhesus (Rh) D prophylaxis on positive direct antiglobulin test (DAT) results and ability of a DAT grade to predict an infant's need for phototherapy., Methods: Laboratory and infant medical records were reviewed for DAT status, DAT grade, interventions for hyperbilirubinemia including phototherapy, blood transfusion, exchange transfusion and intravenous immunoglobulin. Two epochs of DAT results were reviewed, the first in the era prior to Rh D prophylaxis, the second after introduction of standardised Rh D prophylaxis for Rh negative women., Results: A total of 165 DAT-positive infants' medical records were reviewed. The number of positive DAT results increased from 1.5% to 2.3% (P < 0.0001) following introduction of anti-Rh D prophylaxis, the increase related to an increase in anti-D DATs (7.4% to 32% -P < 0.0001). An infant with a DAT grade of 5-8 was 2.6 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (odds ratio (OR), 2.571; 95% confidence interval (CI), 1.225-5.393; P = 0.08) and an infant with a DAT grade of 10-12 was 4.7 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (OR, 4.724; 95% CI, 1.602-13.926, P =0.013)., Conclusions: Rh D prophylaxis has increased positive DAT results, which may increase the number of unnecessary bilirubin measurements. A low or high DAT grade is strongly predictive of whether an infant does or does not require phototherapy. However, an intermediate DAT requires concomitant bilirubin measurements to determine phototherapy requirements., (© 2010 The Authors. Journal of Paediatrics and Child Health © 2010 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

The aim of this study was to determine how many UK maternity units have implemented National Institute for Clinical Excellence (NICE) guidance for routine antenatal anti-D prophylaxis (RAADP). In May 2002, the NICE recommended a policy of RAADP for RhD-negative pregnant women. The policy has the potential to reduce maternal sensitization and prevent deaths from haemolytic disease of the foetus and newborn, but implementation entails considerable clinical, financial and organizational challenges. A postal survey of all 324 UK maternity units was completed in 2005.Responses were received from 91% of units (294 of 324). RAADP was offered by 220 of 294 (75%) and in England and Wales 19% of those offered a single-dose regime. At 12% of maternity units, routine paternal blood group testing was offered. For 84% of maternity units, staff education was offered at the time of implementation. Written patient information was provided at 97% of maternity units and 147 of 217 (69%) returned a copy. We received 60 different leaflets. Three years after NICE guidance was issued, one in four maternity units did not offer RAADP. Among those that do offer RAADP, practice with regard to anti-D administration, paternal testing, provision of written information and staff education varied. Unit and clinician level research is required to understand why.

The aim of this study was to determine the compliance rates for women being offered routine antenatal anti-D prophylaxis in two obstetric units in the UK. Haemolytic disease of the newborn (HDN) is a potentially serious condition that can result in substantial morbidity and sometimes death. Current guidelines recommend that 500 IU anti-D immunoglobulin G (IgG) should be offered to all non-sensitized RhD-negative women at 28 and 34 weeks' gestation in order to prevent the risk of RhD sensitization in pregnancy. Implementing guidance, however, remains a challenge. We conducted a retrospective audit of 207 RhD-negative, non-sensitized pregnant women attending obstetric units during 2004 to assess compliance with national guidance on the provision of antenatal anti-D prophylaxis. Informed consent for routine antenatal anti-D prophylaxis was documented for 185 of these women. In total, 86.5% of women received the two doses of anti-D IgG. The majority of women received their first and second doses within 1 week of 28 and 34 weeks' gestation (87.0 and 86.0%, respectively). Accurate records of prophylactic anti-D IgG were maintained and updated. This audit demonstrates that the level of patient compliance with the two-dose regimen was high.

The serological differentiation of weak D from partial D, D-negative and D-positive is not always unequivocal. Therefore, sequencing of the RHD gene is required in some cases. Very recently, several new differences between RHD and RHCE have been identified which permitted us to design primers close to the exon/intron boundaries of the RHD-exons. We evaluated these primers in 83 D-positive and 18 D-negative blood donors and applied the new method for the characterization of the RHD gene in six individuals with weak D phenotype. The amplification reactions were concordant with serological findings in 100 of 101 donors (99.0%). In one D-positive donor the PCR for exons 2 and 5 gave a negative result, while the sequence of the remaining eight exons was unchanged. By sequencing samples with very weak D serological reactions, we identified weak D type 4.2.2 and weak D type 15, both previously reported to be associated with anti-D-alloimmunization. Consequently, we recommended the selection of D-negative blood in the weak D type 4.2.2 patient, and the provision of Rh prophylaxis for pregnant women with weak D type 15. In summary, a new RHD sequencing method was developed which can be applied if serological reactions are inconclusive.

Anti-RhD immunoglobulin was administered to RhD-negative women based on estimates of fetal bleed size obtained using a direct immunofluorescence flow cytometric technique employing a FITC-conjugated monoclonal human anti-D (BRAD 3). The effectiveness of the dose administered was assessed by (i) measuring the fraction of RhD-positive fetal cells in the maternal circulation at d0, and between d2 and d10 post RhD Ig administration, (ii) quantifying the amount of anti-D detectable in maternal plasma following RhD Ig injection in the perinatal period and (iii) assessing maternal serum for the presence of immune anti-D in follow-up samples taken 3 months to 3 years after delivery. Fifty-four women were assessed, 29 having fetal bleeds in excess of 4 mL. Follow-up samples were received from 20/29 mothers after RhD Ig administration; 43-99% and 69-99% of fetal cells had been cleared by d2/3 and d5/6, respectively, in 14/20 mothers, whereas less than 50% had been cleared in the remaining mothers. Long-term follow-up samples were obtained from eight of the 29 mothers (four with bleeds >/=20 mL, two with bleeds >95 mL): none had detectable anti-D in the serum 4 months to 3 years after delivery despite the persistence of up to 36% fetal RhD-positive cells in the maternal circulation six days after delivery.

Background: Standard post-delivery administration of anti-D, together with further anti-D for events known to result in fetomaternal haemorrhage (FMH) during pregnancy, has reduced the incidence of alloimmunisation in RhD women to 0.83-1.5% in the UK. Residual alloimmunisation occurs mainly for two reasons: i) failure to administer sufficient anti-D at the correct time after known at-risk events, either during pregnancy or at delivery; and ii) alloimmunisation during pregnancy as a result of 'silent' FMH. The RhD antigen is well developed by 6 weeks' gestation and the fetoplacental blood volume increases during pregnancy. Studies show that 3% of pregnant women have FMH in the first trimester, 12% in the second, and 45% in the third. Analysis of alloimmunisation in primigravidae clearly shows that on average, 90% are detectable after 28 weeks' gestation. Additional anti-D prophylaxis during the course of pregnancy, starting at 28 weeks, can reduce alloimmunisation to a minimum by protecting against occult FMH. The identification of intrapartum alloimmunisation as being the 'true' cause of alloimmunisation is best assessed by studying first pregnancies, and rigorous analysis of antenatal anti-D efficacy should preferably include observation in second pregnancies to avoid underestimation of alloimmunisation. Ideally there should be no exclusions, i.e. treating both arms of the study on an 'intention to treat' basis, otherwise there will be an overestimate of efficacy under routine practice conditions. Initial safety concerns about effects of antenatal anti-D on the fetus have not been confirmed in practice., Options: Although there is only one randomised controlled clinical trial (with small numbers) demonstrating a further reduction in alloimmunisation following antenatal administration of anti-D meriting a grade A recommendation (see appendix II), the total body of evidence of efficiency is compelling. Whilst two doses of 300 microg are effective, this is no more so than the single dose in practice, and as it requires considerably more anti-D immunoglobulin, it is probably not cost effective. If a single dose is to be given, it is too late at 34 weeks, and 28 weeks is to be recommended. If divided doses are to be given at 28 and 34 weeks, 50 microg is insufficient, and 100 microg is recommended. Two dose regimes can be recommended, as follows: i) single dose of 300 microg at 28 weeks--the results of the single 300 microg dose in first pregnancies is limited to the Canadian study with observed reduction from 1.6% (45/2768) in concurrent nonrandomised controls to 0.18% (2/1086) in the treatment group. ii) two doses of 100 microg at 28 and 34 weeks--the two controlled studies give similar results in first pregnancies. A reduction in alloimmunisation is seen from 1.11% (4/360) in controls to <0.28% (0/362) in the treatment group in the French study , and from 0.95% (19/2000) in controls to 0.32% (4/1238) in the treatment group in the English study. Whilst anti-D is in limited supply, it is more cost effective to restrict antenatal prophylaxis to first pregnancies. It is also probable that a single dose of 250 microg (as used in Europe) will be as effective in practice as the 300 microg dose, given the limitations of the anti-D quantification assay, and the vial overfill introduced by manufacturers, but this has not been formally proven in clinical trials. The number of RhD deaths is now very low, even with standard postpartum prophylaxis, but there is a systematic underreporting in the UK, due to early fetal deaths being recorded as 'abortion' rather than as haemolytic disease of the newborn (HDN). There have been no systematic studies on the reduction in mortality observed with antepartum anti-D. Nevertheless, it is self-evident that if immunisation is largely prevented, then so will fetal morbidity and mortality.

In the UK a Kleihauer test is routinely performed on all RhD-negative women after the birth of an RhD-positive child to ensure that an adequate dose of anti-D immunoglobulin is given. The results of Kleihauer testing are interpreted to assess the volume of any feto-maternal haemorrhage and additional anti-D immunoglobulin is administered if necessary. A similar procedure is followed ante-natally when incidents occur known to be associated with alloimmunization. The performance of Kleihauer tests is difficult to standardize and there can be problems in interpreting the volume of feto-maternal haemorrhage. The use of flow cytometry to measure feto-maternal haemorrhage is reported to give more accurate and reliable results. This study compared three different Kleihauer methods and two different flow cytometry techniques all performed using the same maternal sample and within a single laboratory. The results demonstrated variability between the Kleihauer tests used and also in the flow cytometry measurements. A well-performed Kleihauer test would still appear to be useful as a screening technique for detection of feto-maternal haemorrhage. However, accurate quantitation of size of feto-maternal haemorrhage is more reliably determined by flow cytometry.

A dynamic model of the action of anti-D immunoglobulin in effecting clearance of Rh D-positive red cells from the circulation of D-negative subjects is presented. The pharmacokinetics of the redistribution of anti-D between injection site, intravascular and extravascular spaces following either intramuscular or intravenous administration is included, also the reaction of anti-D with D-positive red cells in the intravascular space and subsequent circulatory clearance of antibody-coated cells. Numerical computer modelling methods have been used to obtain solutions of the model, using kinetic rate constants which have been derived from previously published experimental data. Selected solutions are presented, chosen for their relevance to (i) clinical situations in which anti-D is used to prevent Rh D immunization of D-negative subjects and (ii) determination of some of the properties of anti-D antibodies which are important for effecting circulatory clearance of D-positive red cells.

Routine antenatal Rh immunoprophylaxis would substantially increase the use of anti-D Ig in the U.K. As availability of anti-D Ig is one factor influencing a decision to introduce routine antenatal prophylaxis, a trial was undertaken to test the efficacy of a lower dose of anti-D Ig than that used in earlier studies. RhD-negative primigravidae were randomized as controls or recipients of two doses of 250iu of anti-D Ig given at 28 and 34 weeks gestation. Blood samples were tested at delivery and at 6 months postpartum for the presence of immune anti-D, and again later if results were equivocal. Nine (1.5%) out of 595 control patients had immune anti-D at follow-up at 6 months and later; 4 (0.78%) of 513 treated women were immunized. It was concluded that, while two doses of 250iu of anti-D Ig may reduce alloimmunization, they are not as effective as two doses of 500iu in a previous trial.

Objective: To identify the reasons behind failures to prevent the development of Rhesus (D) haemolytic disease of the newborn., Design: Retrospective analysis of the case records of all pregnancies that resulted in the birth of an infant with a positive direct antiglobulin test on the cord red cells born to Rh(D) negative women between 1 April 1985 and 31 March 1990., Setting: Obstetric units in the South East Scotland region and the South East Scotland Regional Blood Transfusion Service Antenatal Laboratory., Main Outcome Measures: The causes and clinical consequences of maternal immunisation to the Rhesus (D) antigen., Results: Between 1985 and 1990, 80 pregnancies resulted in the birth of an infant sensitised with anti-D on the cord red cells. There were no deaths due to haemolytic disease, but considerable resources were deployed in obstetric and neonatal care for these pregnancies. Sufficient data were available to categorise the cause of maternal immunisation in 70 pregnancies. Seven cases were due to immunisation by pregnancy before 1970. Sixty-three cases could be attributed to failure of the Rhesus programme: 10 cases (16%) were due to failure to implement the programme adequately, the other 53 cases (84%) were due to failure of the current guidelines to provide adequate protection. Late immunisation in an uncomplicated pregnancy was the single commonest identifiable cause., Conclusions: It is likely that substantial further reductions in Rhesus (D) immunisation and haemolytic disease of the newborn will require changes in the Rhesus prevention programme. In particular the role of antenatal prophylaxis requires detailed consideration.

Between 1950 and 1970 there was a steady decline in the number of infant deaths from rhesus haemolytic disease of the newborn in the Yorkshire Region but no decrease in the number of pregnant women with antibodies. Following the introduction of Rh prophylaxis in 1970, the number of pregnant women sensitized has decreased by 70% and the number of infant deaths by 96%. The number of infants requiring exchange transfusion has also decreased by 70%. During the years 1980 to 1983 there were 163 new cases of maternal sensitization to the D antigen in the Yorkshire Region, 36 were due to failures of administration, 75 were failures of protection and 26 were in primigravidae. Eighteen of the failures of administration occurred after abortion, nine of which were surgical terminations. Antenatal prophylaxis may well have protected 64 (40%) of these 163 women. The number of pregnant women with antibodies other than anti-D now exceeds those with anti-D. The effect of these changes in incidence and clinical severity on the management of Rh D negative pregnant women is discussed.

Fourteen mothers carrying ABO compatible but Rh D incompatible pregnancies experienced large feto-maternal haemorrhages (estimated 188 ml, range 50-400 ml red cells). These were all treated with infusions of fresh frozen plasma containing anti-D at a mean immunoglobulin to fetal cell ratio of 129 i.u. (25.8 micrograms)/ml of fetal cells. At 48 h after the infusion 95% of fetal cells had been removed but 3 to 4 days were required for complete removal. The passively administered anti-D was detectable for up to 6-9 months but not after that time. Four of the 14 women had successful pregnancies subsequently although in two of these anti-C + D was present. Of these, one resulted in a clinically affected baby who survived exchange transfusion.