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Over 200 delegates from hospitals and blood transfusion units around the world attended a consensus conference on anti-D prophylaxis in Edinburgh on 7 and 8 April 1997. The conference was convened jointly by the Royal College of Physicians of Edinburgh and the Royal College of Obstetricians and Gynaecologists. The aims were to reach a consensus on: the current management of rhesus D (RhD) negative women in pregnancy and the future management of such women
The consensus process was fairly rigorous. It was mediated through a panel of independent healthcare and lay professionals. The available evidence in the form of written, oral, and poster presentations were reviewed and opposing views were presented by an advocate and an adversary, each with a seconder. A draft consensus statement, prepared by the panel, was debated by the delegates and the resulting second draft statement with amendments was adopted by the conference. The final consensus statement is now in the public domain.1
Current status of rhesus disease and anti-D prophylaxis in the UK
Perinatal deaths in the UK due to RhD alloimmunisation have fallen a 100-fold since the introduction in 1969 of a policy to administer anti-D immunoglobulin (Ig) to RhD negative women after sensitising events in pregnancy and the birth of RhD positive infants.2 There is no dispute that this represents a dramatic success in preventive medicine. However, rhesus disease has not been eradicated. In the 1990s pregnancy, loss, and death in the first week after delivery due to RhD alloimmunisation is about 50 a year in the UK (position papers presented at the conference).
Opinion was divided at the conference over the acceptability of this level of loss. On the one hand should further efforts be directed to reduce a mortality that is already less than 10 in 100000 pregnancies? Yet the contrary view was also presented—namely, that no loss is acceptable if there are known means of prevention. About one to two in every 100 RhD negative women at risk become sensitised.2There are two main reasons for this3-8: failure of application of current guidelines (see below) and sensitisation by undetected “silent” fetomaternal haemorrhage (FMH) especially in the last 12 weeks of pregnancy.
Current guidelines on anti-D prophylaxis: effectiveness and scope for improvement
The current guidelines were produced by the UK National Blood Transfusion Service IgG Working Party in 19919 and are summarised in table 1. There was general agreement that the failure of full application of these guidelines was a matter of great concern. Compliance failure rates of over 30% have been reported in some studies of anti-D administration for potentially sensitising events in pregnancy.3 4 Of particular concern was the failure to give prophylaxis in RhD negative women with bleeding in early pregnancy, especially when such cases presented to accident and emergency departments rather than to general practitioners or antenatal clinics.5
The dose of anti-D used routinely to prevent sensitisation differences between countries is illustrated in table 2.
The consensus panel recommended that the UK guidelines of 19919 should at present remain the reference standard for good clinical practice and that there should be no change to the dose principle of 500 IU for up to 4 ml of transfused fetal red blood cells. Studies of rhesus sensitised infants have variably reported apparent therapeutic failure of anti-D for potential sensitising events during pregnancy of between 18 and 66% (position papers presented at the conference). Clearly, the use of a higher dose of 1500 IU might prevent some of these cases. It is impossible to estimate accurately the size of this effect and its cost implications, but it was unfortunate that there was not more extensive debate on this issue at the conference. It must be acknowledged, however, that even if the higher (1500 IU) dose were to be used it would not protect those women who have a postnatal FMH of over 12 ml (estimated at over 200 women annually in the UK).
The 1991 guidelines are currently being revised by representation of the British Blood Transfusion Society’s Special Interest Group on Haemolytic Disease of the Newborn and of the Royal College of Obstetricians and Gynaecologists. There are three main areas where these guidelines might differ from current recommendations—namely, routine antenatal anti-D prophylaxis, first trimester prophylaxis, and inadvertent transfusion of RhD positive blood to a RhD negative woman.
Apart from failures to administer anti-D IgG following sensitising events during pregnancy, the panel also expressed concern over the high incidence of failures to estimate the size of FMH by Kleihauer or alternative tests. In one study of sensitising events after 20 weeks this test was performed in only 10% of cases (position papers presented at the conference).
Routine antenatal anti-D prophylaxis
Over 90% of spontaneous (absence of overt sensitising event) FMH during pregnancy occurs in the last trimester (position papers presented at the conference). There is good evidence from many trials that antenatal prophylaxis significantly reduces the incidence of sensitisation by a factor of between 2 and 16 fold.6-8 13-18 The lower improvement rates were in those trials which used either single dose regimens or low dose anti-D (250 IU) in double dose regimens. In the light of this very strong evidence the panel proposed that because all RhD negative pregnant women are at risk from hidden bleeds, they should be given anti-D IgG prophylactically.
The critical question is, what is the cost effectiveness of this strategy? Estimates of the costs of current antenatal interventions in the UK in the absence of routine antenatal prophylaxis were presented at the conference (table 3). There are also the costs of neonatal care after delivery. Apart from the financial costs there are the costs incurred in terms of complications from such medical interventions. For example, approximate fetal loss rates are 5% for intrauterine transfusion, 1.5% for fetal blood sampling, and 0.3–0.5% for late amniocentesis. Determining cost effectiveness is very difficult as the figures will be influenced by factors such as the population studied, dose regimens, and outcome measures.
A review of the published cost effectiveness data was presented at the conference. The general conclusions from this review were: routine antenatal prophylaxis for all RhD negative pregnant women will increase costs. Cost effectiveness is influenced by the dose(s) of anti-D used, and programmes restricted to women who have not had a baby before are more cost effective and in certain theoretical models may result in a net cost saving.
In summary, the panel felt that the paucity of recent cost effectiveness studies made it difficult to draw definitive and accurate conclusions about the benefits of extending the current policy to include routine antenatal prophylaxis. The cost of offering routine antenatal prophylaxis will depend on the dose and frequency regimen used. Current evidence suggests that antenatal prophylaxis has the potential over time to save more resources if restricted to pregnant women without a living child, although this will involve a modest degree of preliminary investment to increase the supply of anti-D IgG.
Increasing the programme to include all RhD negative pregnant women will have a considerable net cost. It must be acknowledged, however, that the approximate range of possible costs presented at the conference per life year saved still compared favourably with the costs of other interventions in the NHS. Furthermore, the panel felt that, while the greatest cost benefits of routine prophylaxis had been theoretically calculated for childless mothers, it could not be ethically or economically justified to limit the policy to that group of women.
The most effective dosage and schedule of prophylaxis has to be determined. The two main options are: 500 IU anti-D at 28 and 34 weeks or a higher dose (1250 IU) of anti-D early in the third trimester
It is anticipated that UK blood transfusion centres will be able to meet the requirements for supply of polyclonal anti-D at least for a programme in primigravidae. In the long term, however, it is reasonable to expect that the supply will be sufficient to protect all RhD negative women routinely. Until a safe monoclonal product is available the principal source of donors will have to be sensitised men and women. No serious adverse reactions have been reported in women receiving intramuscular anti-D IgG, but it is important that the viral and other safety issues raised by changes in product manufacture are kept under rigorous review. Furthermore, in introducing antenatal prophylaxis the panel suggests that health authorities should first check on compliance with current guidelines. If initially there is insufficient anti-D IgG for all women at risk, primigravidae should be given priority. Early consultation with professionals in primary care will be essential.
Current status of monoclonal Anti-D
The authors of the 1991 guidelines for anti-D prophylaxis hoped that an effective monoclonal anti-D would soon be available to supplement polyclonal anti-D, and that there would be sufficient quantities to allow antenatal prophylaxis to be started. In 1997 it seems that monoclonal preparations, of which supply would be theoretically limitless, could, in principle, replace polyclonal anti-D, yet only phase 1 trials are at present complete on monoclonal preparations. It is not yet certain if these preparations will be safe and efficacious, reliable or affordable. There may be advantages from an intravenous preparation that can also be given intramuscularly. It is also uncertain how long it will be before monoclonal products are available in sufficient quantity, and whether they will be acceptable to regulators. The process of introducing monoclonal products and possibly phasing out polyclonal anti-D will need to be agreed nationally, and will require a comparative trial. Polyclonal products should not be phased out until the monoclonal supply has been shown to be secure.
Other issues considered
The first was whether anti-D should be used for the treatment of immune mediated thrombocytopenia. The panel accepted that anti-D IgG may have a place in the treatment of RhD positive patients who have not had their spleens removed, especially children with chronic immune thrombocytopenia, and that in these patients it may have a similar role to high dose intravenous immunoglobulin. However, with current UK practice it is only likely to be used in a small number of patients. In the UK an imported anti-D IgG preparation is available for use in immune mediated thrombocytopenia on a named patient basis.
The second issue related to the ethical considerations of using immunised volunteers to provide anti-D. The conference concluded that the donor should be able to make a full and free informed choice before consenting to the immunisation procedure. Voluntary consent to this procedure must be genuine and explanation geared to capacity to understand and act on what is required. A comprehensive information leaflet should be made available for prospective donors. There will probably continue to be a need for immunised donors well into the 21st century, and until the safety, efficacy, and quality of monoclonal anti-D is established to the standard of European regulatory requirements. The question of compensation for non-negligent harm is vexed but clearly some effective and transparent arrangement to compensate volunteers is desirable.
The conference considered present and future issues relating to the management of RhD negative pregnant women in a thorough, balanced, and fair way. Some cynics have criticised the conclusions of the conference panel because the blood products industry were co-sponsors and inevitably this would have been expected to have led to a recommendation to increase the use of anti-D. This is unfair criticism. The evidence of scientific effectiveness of routine anti-D prophylaxis is very robust and on that conclusion alone, the practice must be recommended.
The important question providers of health care will have to answer is: is the present hidden or spontaneous RhD sensitisation rate acceptable? If the answer to that is “no” then offering routine anti-D prophylaxis to RhD negative pregnant women in the third trimester may be cost effective in the long term. The dose which seems to be preferred is 500 IU anti-D at 28 and 34 weeks.
Finally, and as a more immediate priority, all professionals involved in pregnancy care should improve the implementation of the 1991 guidelines. Specifically, there needs to be a tightening up of the practice of the administration of anti-D to RhD negative women and the use of Kleihauer testing at the time of sensitising events in pregnancy. This advice is especially relevant to those working in accident and emergency departments and in primary care.
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