Indications for anti-D use to reduce risk of HDFN

Prophylactic anti-D immunoglobulin (anti-D Ig; 500 iu) is generally given within 72 hours of a postsensitising event (PSE), with additional dosing for PSEs after 20 weeks’ gestation guided by fetomaternal haemorrhage (FMH) estimation. A single dose of 1,500 iu is commonly used for routine antenatal anti-D prophylaxis (RAADP), given between 28 and 30 weeks’ gestation, as recommended by the National Institute for Health and Care  Excellence (NICE).¹

Alloimmunisation to the D antigen resulting in serious sequelae in offspring still occurs, in particular owing to late or missed administration of anti-D Ig. Anti-D Ig is also recommended following transfusion of D-positive blood components to D-negative individuals with  childbearing potential.²

Current antenatal practice in the UK recommends all D-negative pregnant women are offered RAADP, despite approximately 40% of these women carrying a D-negative fetus.¹ However, high-throughput non invasive prenatal testing (NIPT) for fetal RHD genotype is now available in the UK and is recommended as a cost-effective option to guide antenatal prophylaxis with anti D Ig.³

NIPT involves extraction of cell-free fetal deoxyribonucleic acid (cffDNA) from a maternal blood sample and can be performed as early as 11 weeks’ gestation. The fetal D-type predicted by the assay can then be used to guide appropriate administration of anti-D Ig and avoid unnecessary exposure.

Reporting adverse events in the UK

Serious Hazards of Transfusion (SHOT) is the professionally led, independent, confidential UK haemovigilance reporting scheme that began in 1996, collecting and analysing anonymised information on transfusion-related adverse events and reactions. Where risks and problems are identified, SHOT produces recommendations to improve patient safety published in the Annual SHOT Report. 

The data from SHOT since reporting began in the 1990s is immensely valuable in supporting learning from errors and near miss events.

Anti-D Ig is made from human plasma and is classed as a medicinal product, with untoward clinical reactions such as allergy reported via the Medicines and Healthcare products Regulatory Agency’s Yellow Card scheme. Adverse events involving anti-D Ig prophylaxis, post-PSE and RAADP, and in particular any procedural errors, are reportable to SHOT. 

Anti-D Ig errors

SHOT data on types of errors

Failure to administer anti-D Ig within the recommended time frames or giving an insufficient dose reduces the efficacy of prophylaxis with risk of development of immune anti-D. Annual SHOT reports have identified system failures resulting in omission and delays in giving anti-D Ig, administration errors and other events involving anti-D Ig management.⁴

The data from SHOT since reporting began in the 1990s is immensely valuable in supporting learning from errors and near miss events. SHOT has also been collecting data involving errors relating to cffDNA screening since 2017. This data demonstrates the increased complexity  introduced by the screening process.

A total of 3,741 anti-D Ig cases were reported between 2011 and 2020. Of these cases, 71.2% (2,662) related to omission/late administration of anti-D Ig for RAADP and following PSE. In 15 cases (reported between 2017 and 2020), RAADP was omitted based on cffDNA incorrectly predicting the fetus as D-negative, where samples taken from the cord at delivery tested D-positive. In 181 (4.8%) cases, anti-D Ig was given inappropriately to a mother with a D-negative fetus. Of these, 12 (reported between 2017 and 2020) involved administration of RAADP based on a cffDNA incorrectly predicting the fetus as D-positive, while samples taken from the cord at delivery tested D-negative.

Other errors reported to SHOT included administration to D-positive women (207, 5.5%), administration to women with immune anti-D (194, 5.2%), incorrect dose (156, 4.2%), product expired, out of temperature control or wrongly labelled (213, 5.7%) and  miscellaneous (128, 3.4%). 

Reasons for errors in anti-D administration and action needed

Omissions and delays occur because of failures in communication, discharge of patients before anti-D Ig is given, lack of understanding regarding the requirement for anti-D Ig and assumptions in care. Failure or delay in administration puts the woman at risk of developing immune anti-D, which can lead to HDFN in subsequent pregnancies.

SHOT has developed an aide memoire to remind staff when anti-D Ig should be administered,5 but it is incumbent on all maternity units to review their care pathways and develop robust systems to address avoidable errors. These factors have been explored further in the SHOT Bite.⁶

British Society for Haematology (BSH) guidelines state that a minimum of 250 iu anti-D Ig should be given for PSE up to 20 weeks.² However, this dose is no longer available in the UK. This has contributed to some errors in administration, with clinical staff attempting to split a 500 iu dose. It should be noted that where guidelines state ‘minimum’, a dose of 500 iu or 1,500 iu is acceptable. Anti-D Ig is generally given intramuscularly, but products that can be given intravenously are available and should be utilised where intramuscular administration is not appropriate. 

Errors in relation to cffDNA screening

The cffDNA screening program undoubtedly reduces unnecessary exposure to anti-D Ig but SHOT data demonstrates that it is introducing new challenges to the management of D-negative pregnancies. It must be noted that reporting of discrepant results to SHOT may not be comprehensive and uptake in screening is not yet universal across the UK. As more organisations implement cffDNA screening, local processes should be in place to ensure discrepant results are managed appropriately.

The screening test offered by NHS Blood and Transplant is designed to minimise false D-negative results to <0.1%. In up to 2% of tests, the result will be incorrectly predicted to be D-positive despite the baby in fact being D-negative. This small false-positive rate when using NIPT means that only 2% of D-negative women receive antenatal prophylaxis unnecessarily, rather than 40% without using the NIPT.7 False-positive cffDNA results may occur as a result of rare, silent or variant Rh genes, or weak D alleles, vanishing twin or extraneous low-level DNA contamination of the sample. Where a fetal D-positive result has been reported but the cord blood tests D-negative, this should be reported to the testing laboratory and SHOT. 

Investigations at the local level could include wrong blood in tube (WBIT; mother or cord) and weak D (cord sample), although this is not included in current guidelines. All cases of apparent falsenegative cffDNA results should be reported to the testing laboratory, along with blood samples from mother and baby. They should also be reported to SHOT. Local investigations should include WBIT (cord sample) and anti-D Ig prophylaxis should be given as appropriate. 

Immune anti-D

A questionnaire was introduced from January 2013 to collect information about women who have developed a new immune anti-D that is detected during pregnancy, at delivery or in a subsequent pregnancy. Cases of immune anti-D detected in women with previous pregnancy (PP) and those with no previous pregnancy (NPP) were analysed for any relationship to errors in prophylactic anti-D Ig management, maternal weight or gestation at delivery. This new initiative sought to address the lack of efficacy data for anti-D Ig prophylaxis and provide a better understanding of the causes of continuing anti-D sensitisations.

From 2013 to 2020, a total of 377 cases of sensitisation were reported – 105 cases occurred in women with NPP and 272 in women with PP. The data illustrate missed opportunities where pregnancy management is not ideal including delay in RAADP, insufficient dosing and omission of prophylaxis. A total of 69 PSE have been reported in the preceding pregnancies, of which only 46 (66.6%) were managed correctly. Furthermore, ideal management does not equate to no sensitisation. Delivery beyond 40 weeks and obesity may be risk factors for sensitisation. A comparison to the national maternity data set is required to determine if women who are obese or deliver beyond 40 weeks are over-represented.

A focused approach to ensure treatment decisions are right for D-negative women is necessary to prevent sensitisation. A review of the material available to support practice is underway. The possibility of an electronic application to support decision making should be considered. In the interim, hospitals should align local policies with the BSH addendum that signposts the more recent NICE Guidance 126 and 140 (published in 2019). Electronic health record providers and hospitals who plan to implement or continue to develop this should map the care plan for D-negative women in pregnancy and post-partum, developing intelligent pathways that support effective management and decision making.

Conclusions

Implementation of programs for antenatal and postnatal anti-D Ig prophylaxis has led to a significant reduction in the frequency of D alloimmunisation and associated fetal/neonatal complications. SHOT data demonstrates that there are missed opportunities for anti-D Ig prophylaxis where management is not ideal.

Errors can be prevented with robust management policies and processes in place, improved communication between all healthcare professionals involved in patients’ care, and staff adhering to the necessary checks and taking appropriate and timely actions. However, these complex pathways are likely to benefit from electronic clinical decision support systems.

Women should be educated about PSE and the importance of reporting these within 72 hours of occurrence for anti-D Ig to be effective.

Traceability and accurate documentation are paramount to patient safety. RAADP should be given to all eligible RhD negative women in accordance with NICE guidance and with the predicted D-type of the fetus from cffDNA testing. This is a field where our understanding is constantly evolving. As more maternity services continue to adopt NIPT, reporting will increase leading to additional learning which will help identify aspects for improvement.

Women should be educated about PSE and the importance of reporting these within 72 hours of occurrence for anti-D Ig to be effective. However, data from SHOT, as discussed in this article, has shown that ideal management with anti-D prophylaxis does not prevent sensitisation in all cases, and adherence to antibody testing regimes is vital for identification and appropriate fetal monitoring.

Questions remain regarding the effect of maternal obesity and delivery beyond 40 weeks on the efficacy of anti-D prophylaxis. Haemovigilance reporting is an ongoing exercise and it is vital that the learning from SHOT reports is embedded into clinical practices, improving safety for patients. 

References available.