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Anti-D: a matter of life or death?

21 January, 2013

Anti-D: a matter of life or death?

Thanks to anti-D , the number of deaths due to HDFN has fallen dramatically. But are too many mistakes are still being made?
Midwives magazine: Issue 1 :: 2013

Thanks to the administration of anti-D immunoglobulin, the number of deaths due to HDFN has fallen dramatically. But Tony Davies argues that too many mistakes are still being made. 

Anti-d being administered

There is no question that the impact of anti-D Ig prophylaxis has been immense since it was first introduced for postnatal use in 1969. Over the next 20 years, deaths due to haemolytic disease of the fetus and newborn (HDFN) caused by immune anti-D fell from 46 per 100,000 pregnancies to 1.6 per 100,000 (Pilgrim et al, 2009; Crowther et al, 2000).

How does it work?
The principle behind anti-D Ig prophylaxis is simple – administer an injection after a potentially sensitising event (PSE) to prevent a woman developing her own immune anti-D in future pregnancies. The anti-D binds to RhD positive red cells, which are then removed from the circulation before they can trigger antibody production.

When should it be given?  
Delivery is the time of greatest risk for fetal cells crossing the placenta and entering the maternal circulation (fetomaternal haemorrhage, or FMH). In most cases, the volume of fetal cells is less than 4ml (the volume that a 500 IU dose of anti-D will cover), but larger FMH may occur with traumatic deliveries including CS, manual removal of the placenta and in twin pregnancies.

Anti-D Ig is administered to non-immunised RhD negative women as soon as possible after delivery if the baby is RhD positive, and should always be given within 72 hours. Even if more than 72 hours have elapsed since delivery, there is value in giving anti-D up to 10 days later as sensitisation could still be prevented.

If the baby is RhD negative, no anti-D Ig prophylaxis is required, though some units have opted for blanket administration to RhD negative women to ensure that none are missed while waiting for results. This may prove a costly option in the long term, as global supplies of suitable plasma from which to make anti-D Ig are dwindling.

In the case of intrauterine death or stillbirth, where a sample from the baby cannot be obtained, a standard dose of anti-D Ig should be administered and a Kleihauer test performed in case more is needed.

It is imperative to recognise PSEs during the antenatal period and to consider anti-D Ig prophylaxis. PSEs include abdominal trauma (especially during the third trimester), threatened or actual miscarriage, antepartum haemorrhage, termination of pregnancy, ectopic pregnancy, evacuation of molar pregnancy, invasive prenatal diagnosis or other intrauterine procedures, stillbirth and intrauterine deaths.

How much to give?
A standard dose of 500 IU of anti-D will cover a bleed of up to 4ml of fetal red cells, but for larger bleeds, additional doses are required. For this reason, it is important to check the size of the FMH at delivery and for PSEs after 20 weeks’ gestation using a Kleihauer test in the first instance or referring a sample for flow cytometry.

In addition to the established practice of giving anti-D Ig at delivery, NICE recommends the implementation of routine antenatal anti-D prophylaxis (RAADP) (NICE, 2002), and this has resulted in the rate of sensitisation further reducing from >1% to 0.2%. RAADP may be administered as a two-dose regime at 28 and 34 weeks’ gestation, or as a single (larger) dose between 28 and 30 weeks’ gestation.

Raising standards
The Serious Hazards of Transfusion (SHOT) haemovigilance scheme collects reports of failures in the requesting and administration of anti-D Ig and has identified some disturbing trends. The number of incidents reported has increased every year, from just 17 in 2000 to 249 in 2011, and this should be viewed, in part, as a good thing, illustrating an increased awareness of the benefits of learning from adverse events.

However, the reports continue to show that mothers and babies are being put at risk by non-adherence to the national guidance (RCOG, 2011; Parker et al, 2006). The same mistakes are being made repeatedly by both clinical and laboratory staff, particularly failure to follow basic procedures and to take into account laboratory records or reports, and poor communication, decision-making and understanding of the principles.

It is notable that 50% of the reports that SHOT analyses relate to omission or late administration of anti-D Ig, which has the greatest potential for future fetal morbidity or death, and that 71% of the cases involve midwives. Some incidents are clearly due to systems failure rather than individual error, and seem to result from the sheer speed with which women move through the system from delivery to discharge, so that anti-D administration is often overlooked. However, equally as many cases result from an apparent lack of knowledge about when and how much anti-D Ig should be administered during pregnancy.

There is also misuse and misinterpretation of the Kleihauer test (which is performed after 20 weeks’ gestation solely to see if more than the standard dose of anti-D Ig is required), as well as confusion between administration of RAADP and administration in response to a sensitising event. Anti-D Ig must still be administered in response to a PSE, even if the woman has received or is due to receive her RAADP and vice versa.

SHOT data suggests a need for improved education and training. There is an excellent anti-D educational resource, with modules for both laboratory and clinical staff, in the Learn Blood Transfusion e-learning programme.

The easy advice is: ‘If in doubt, give anti-D Ig.’ You cannot (within reason) overdose with it and there is no evidence that repeated large doses have any effect on the baby.
We seem almost blasé about HDFN these days, as many people believe it has ‘gone away’ with use of anti-D Ig prophylaxis, and very few younger midwives, nurses or doctors have ever seen a case requiring exchange transfusion, which was very common only a few years ago.

Babies at risk
There is, however, a ‘wake-up call’ in the 2011 SHOT annual report, which details two cases of women who developed immune anti-D following delay or omission of prophylaxis during pregnancy, and a further seven cases where immune anti-D was misinterpreted as residual prophylactic anti-D Ig by a combination of laboratory error and failure of the clinical area to follow up laboratory requests for repeat samples. Six of these seven cases resulted in babies being born with varying degrees of HDFN; three requiring urgent transfusion support.

While anti-D Ig is a prescription-only product, midwifery exemption allows qualified midwives to administer it in the course of a woman’s care without a separate prescription by a medical officer. The product is made from pooled plasma from non-UK blood donors with high levels of anti-D, and there is a very small residual risk of blood-borne infections or allergic reactions. Because of this, informed consent should always be obtained prior to administration and a full audit trail is mandatory – both in the hospital transfusion laboratory computer and medical records – including the prescriber/midwife, the batch number, the dose, the date and time of administration. Midwives should also familiarise themselves with the particular products and doses available in their hospitals, as this may vary according to local policy. A generic flowchart to support appropriate use of anti-D Ig is available to download from the SHOT website.

Approximately 40% of RhD negative women will be carrying an RhD negative child and therefore should not need prophylactic anti-D Ig. Techniques are now available to test a sample of maternal blood for fetal DNA, enabling accurate prediction of the fetal RhD type early in pregnancy and this will surely become standard practice before long.

Effective provision of anti-D Ig prophylaxis can only be improved by laboratory and clinical staff working in partnership – it is up to us all to ensure we communicate effectively and that robust local protocols are implemented to reflect well-established national guidance.Tony Davies
Transfusion liason practitioner, NHS Blood and Transplant

Illustrations: Brett Ryder


Bolton-Maggs PHB (Ed.) and Cohen H on behalf of the Serious Hazards of Transfusion (SHOT) Steering Group. (2012) The 2011 Annual SHOT Report. SHOT: Manchester: 82-90. See: www.shotuk.org/wp-content/uploads/2012/07/SHOT-ANNUAL-REPORT_FinalWebVersionBookmarked_2012_06_22.pdf (accessed 23 January 2013).

Crowther C, Middleton P. (2000) Anti-D administration after childbirth for preventing Rhesus alloimmunisation. Cochrane Database of Systematic Reviews 2: CD000020.
NICE. (2002) Guidance on the use of routine antenatal anti-D prophylaxis for RhD-negative women. Technology Appraisal Guidance – No. 41. NICE: London.

Parker J, Wray J, Gooch A, Robson S, Qureshi H. (2006) Guidelines for the use of prophylactic anti-D immunoglobulin. British Committee for Standards in Haematology: London.

Pilgrim H, Lloyd-Jones M, Rees A. (2009) Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation. Health Technol Assess 13(10): iii, ix-xi, 1-103.

RCOG. (2010) The management of gestational trophoblastic disease. Green-top Guideline 38. See: www.rcog.org.uk/files/rcog-corp/GT38ManagementGestational0210.pdf (accessed 23 January 2013).

RCOG. (2011) The use of anti-D immunoglobulin for rhesus D prophylaxis. Green-top Guideline 22. See: www.rcog.org.uk/files/rcog-corp/GTG22AntiD.pdf (accessed 23 January 2013).

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