At a conference convened by the Royal College of Physicians of Edinburgh
and the Royal College of Obstetricians and Gynaecologists, a consensus
panel considered specific issues relating to anti-D prophylaxis in the
UK. This statement is based on presentations given at the meeting, published
research and expert opinion.The panel reached the following conclusions:
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Perinatal deaths due to RhD alloimmunisation have fallen a hundred-fold
since the introduction in 1969 of a policy to administer anti-D
IgG to RhD-negative women after sensitising events in pregnancy
and the birth of RhD-positive infants. In the 1990s pregnancy loss
and death in the first week after delivery due to RhD alloimmunisation
is in the order of 50 per year in the UK.
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RhD alloimmunisation still occurs. One to two of every 100 RhD-negative
women at risk still become sensitised. This appears to be for two
main reasons: 1) some women do not receive the benefit of the current
policy, and 2) women are sensitised by small bleeds from the fetus,
mainly in the last twelve weeks of pregnancy, which go undetected.
Current guidelines on anti-D prophylaxis - are they effective, can
they be improved?
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The panel is concerned that there is abundant evidence that
the guidelines are not being fully applied.
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The generally accepted UK guidelines are Recommendations For The
Use Of Anti-D Immunoglobulin (National Blood Transfusion Service
Immunoglobulin Working Party, 1991). The panel recommends that these
should at present remain the reference standard for good clinical
practice and that there should be no change to the dosage principle
of 500iu for 4ml of fetal red blood cells. We are reassured to learn
that there is an expert group currently undertaking review and revision
of the current guidelines, with particular attention being given to
the use of anti-D IgG in the first trimester of pregnancy. Failures
of compliance are particularly common following potentially sensitising
events during pregnancy, both in respect of the administration of
anti-D IgG and the estimation of size of feto-maternal haemorrhage
(FMH) by Kleihauer, or alternative, tests.
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Awareness of the need for anti-D IgG and a Kleihauer (or alternative)
test is essential among staff involved in the care of pregnant women
in obstetric and midwifery units, and also in A&E departments
and in primary care.
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It is recommended that information leaflets about the guidelines
should be given to RhD-negative women and their partners, and relevant
health professionals.
Antenatal anti-D prophylaxis - is it worthwhile, and can we afford
it?
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A current recommendation is that anti-D IgG should be given after
events signalling the possibility of FMH. The panel believes that
routine antenatal anti-D prophylaxis is of proven benefit and that
this would significantly reduce levels of RhD alloimmunisation. The
currently available studies however make it difficult to estimate
the scale of the reduction.
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The panel proposes that because all RhD-negative pregnant women
are at risk from hidden bleeds, they should be given anti-D IgG prophylactically.
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A paucity of recent cost-effectiveness studies makes it difficult
to make definite and accurate statements regarding the efficiency
of extending the current policy to include routine antenatal prophylaxis.
The cost of offering routine antenatal prophylaxis will depend on
dose and frequency. Estimates of cost per dose vary.
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Evidence to date suggests that antenatal prophylaxis has the potential
over time to save more resources than it costs if restricted to primigravidae*,
although this will involve a modest degree of preliminary investment
in order to increase the supply of anti-D IgG. Increasing the programme
to include all RhD-negative pregnant women will have a positive net
cost which might be considerable, but the cost per life year saved
is still likely to compare favourably with other NHS interventions.
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The panel considers there to be no effective argument against protecting
all RhD-negative women, as opposed to just primigravidae. While the
greatest cost benefits of routine anti-D IgG prophylaxis have been
demonstrated in primigravidae, it cannot be ethically or economically
justified to limit the policy to this group of women.
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It is expected that UK blood transfusion centres will be able to
meet requirements for supply of polyclonal anti-D at least for a programme
in primigravidae. In the long term however, it is reasonable to expect
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.
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It remains to be decided which dosage and schedule of prophylaxis
is the most effective. There are two main options - a dose of 500iu
at 28 and 34 weeks, or alternatively a single larger dose early in
the third trimester. Both seem to work.
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In introducing antenatal prophylaxis we suggest 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.
Monoclonal anti-D - is it safe, will it work and can it replace
polyclonal anti-D?
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In 1991 the guidelines authors 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 appears that:
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Monoclonal preparations, of which supply would be theoretically
limitless, could in principle replace polyclonal anti-D.
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Only Phase I 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.
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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.
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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
Should anti-D be used for the treatment of immune-mediated thrombocytopenia?
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The panel accepts that anti-D IgG may have a place in the treatment
of RhD-positive non-splenectomised patients, 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 there is an imported anti-D IgG preparation
available for use in immune-mediated thrombocytopenia on a named-patient
basis.
Ethical considerations of anti-D provision from immunised volunteers
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The donor should be empowered 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.
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It is likely there will 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.
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The question of compensation for non-negligent harm is vexed but
clearly some effective and transparent arrangement to compensate volunteers
is desirable.
* For this purpose we include multigravid women without
a living child.
