Intended for healthcare professionals

Editorials

Preventing Rh immunisation

BMJ 1994; 309 doi: https://doi.org/10.1136/bmj.309.6949.213 (Published 23 July 1994) Cite this as: BMJ 1994;309:213
  1. E A Letsky,
  2. M De Silva

    Without prophylaxis, about one in six Rh negative women who deliver a Rh positive infant will develop anti-D antibodies from fetomaternal haemorrhage occurring either during pregnancy or at delivery.1 Since the introduction in 1969 of anti-D immunoglobulin given after delivery the incidence of haemolytic disease of the newborn due to anti-D antibodies has plummeted. In Britain, however, the rate of RhD sensitisation is still unacceptably high, at around 1.5%; in other words, more than 1000 Rh negative women each year develop anti-D antibodies in association with the delivery of a Rh positive infant.

    No universal policy exists for postnatal prophylaxis. The standard dose of anti-D immunoglobulin and whether tests are undertaken to assess the size of the fetomaternal haemorrhage vary in different countries. For example, 300 μg anti-D immunoglobulin is the standard dose in the United States, 100-120 μg in Canada, and 200-250 μg in many European countries except Britain and the Republic of Ireland, where the dose is 100 μg (500 IU). Studies have shown that 99% of women have a fetomaternal haemorrhage of less than 4 ml at delivery,2,3 and 100 μg is capable of suppressing immunisation from 5 ml Rh positive red cells. The Medical Research Council's first dosage trial showed that 100 μg anti-D immunoglobulin is as effective as both 260 μg and 300 μg in preventing Rh alloimmunisation after delivery.4 This formed the basis for the British policy to give 100 μg anti-D immunoglobulin (???)postnatally and to perform a test to identify women with large fetomaternal haemorrhages who would need additional immunoglobulin.

    A recent note for guidance from the Committee for Proprietary Medicinal Products states that a standard postnatal dose of 1000-1500 IU (200-300 μg) anti-D immunoglobulin should be used for postnatal nmunoprophylaxis, without a routine test to detect the doze of the fetomaternal haemorrhage.5 This recommendation mentation has caused confusion among haematologists and obstetricians, as well as among hospital managers keen to reduce laboratory costs by giving a higher dose of anti-D immunoglobulin and abandoning tests considered to be unecessary. Unfortunately, this European Commission commendation does not take account of the 0.3% of Women with fetomaternal haemorrhage greater than ml.1(/???) If Britain adopts this policy, then each year over 200 Rh negative women who deliver Rh positive infants will receive less protection than they do now.

    The main cause of Britain's continuing relatively high sensitisation rate is the failure to identify RhD negative women at risk and to give the standard postnatal dose within 72 hours of delivery. The Dutch claim of a very low rate of sensitisation after delivery though no antenatal treatment is given must partly be due to their failsafe system of giving anti-D immunoglobulin postnatally.6 Even with meticulous immunoprophylaxis after delivery, immunisation occurs in about 1.0% of women in Britain due to small fetomaternal haemorrhages that occur during pregnancy.7 For these women prophylaxis after delivery is too late. Studies in Britain7 and Canada8 have shown that antenatal prophylaxis could reduce sensitisation to less than 0.1%. Though antenatal prophylaxis has routinely been given in North America for more than 10 years with good results, only a few obstetric units in Britain offer antenatal prophylaxis to Rh negative women. This can no longer be justified by the shortage of anti-D immunoglobulin that existed when postnatal prophylaxis was introduced.

    The manufacturers of all preparations of anti-D immunoglobulin recommend that some way of quantifying fetal cells should be used to calculate the right dose. Tests to estimate the size of the fetomaternal haemorrhage are recommended in the United States,9 Canada,10 and Britain but not in many other European countries. While tests that specifically identify Rh positive red cells are commonly used in the United States, the Kleihauer acid elution test that detects red cells containing fetal haemoglobin is used in both Britain and Canada. The Association of Clinical Pathologists' method for Kleihauer testing has not been updated since 1978,11 and its quality assurance has been neglected. The organisers of Britain's national external quality assurance scheme in blood group serology are, however, aware of this deficiency and are planning exercises in Kleihauer testing later this year.

    In this week's journal Duguid and Bromelow draw attention to the limitations of the Kleihauer test (p 240).12 One criticism is that it identifies red cells containing fetal haemogloblin rather than RhD positive red cells. The small amount of fetal haemoglobin that persists in the blood of normal adults is confined to a few red cells called “F cells,” and the slightly increased concentrations of fetal haemoglobin observed in all pregnant women (maximal at 18-22 weeks' gestation)13 results from an increase in F cells, each of which contains no more than 20% fetal haemoglobin. These F cells can be reliably detected only by sensitive fluorescence antibody techniques. With appropriate controls, these maternal F cells are unlikely to be confused microscopically with fetal cells, which have a content of over 80% fetal haemoglobin, stain deeply, and are refractile. In women with hereditary persistence of fetal haemoglobin, sickle cell anaemia, and homozygous ß thalassaemia for which they have not received transfusions, cells with a high fetal haemoglobin content may be mistaken for fetal red cells. But in Britain women with these disorders who become pregnant are relatively few, and they are likely to have been identified before delivery.

    Flow cytometry and fluorescence activated cell sorting may be used to measure fetal cells in the maternal circulation, but these methods are not available in all laboratories. The Kleihauer test is simple and inexpensive and can be performed by any laboratory.

    Duguid and Bromelow highlight a matter of even greater general concern regarding the reporting of results. None of the laboratories in their survey provided any clinical interpretation or recommendations regarding treatment as part of the laboratory report. For effective care, however, laboratories need to provide not only the results of tests but also interpretation and advice regarding treatment.

    The Committee for Proprietary Medicinal Products provides only guidance, and each country in the European Union is free to implement its own policy. So, rather than following a recommendation of unproved benefit, it would be more appropriate to direct our efforts in Britain towards carefully identifying women requiring postnatal prophylaxis and introducing routine antenatal prophylaxis at least in the first at risk pregnancy.

    Monoclonal anti-D immunoglobulin is now undergoing clinical trials and in a few years may be an unlimited, safe, and inexpensive therapeutic agent for immunoprophylaxis. If this happens then giving sufficiently large doses of antenatal and postnatal anti-D immunoglobulin may safely eliminate Kleihauer testing.

    References

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