Rhesus (Rh) incompatibility, in particular Rh(D) incompatibility, is a major cause of potentially severe haemolytic disease of the newborn, although other blood group antibodies may also cause the disease.1 The use of anti-D immunoglobulin to suppress the production of anti-D antibodies in a Rh(D)-negative mother in response to leakage of red blood cells across the placenta from a Rh(D)-positive fetus has produced a major reduction in the incidence of this disorder.1
Prophylaxis. Postnatal prophylaxis of Rh(D)-negative mothers following the birth of a Rh(D)-positive infant is well established. In 1971, WHO2 suggested a standard dose of 200 to 300 micrograms but stated that a 100-microgram dose was likely to have a success rate only slightly inferior to that of a 200-microgram dose, thus allowing optimum use to be made of a limited resource. Clinical experience in the UK has confirmed the efficacy of the 100-microgram (500 units) dose and this is the amount officially recommended in the UK in such situations.3
Despite the success of anti-D immunoglobulin prophylaxis, sensitisations have continued to occur.4 There are several possible reasons for this. Failures may occur when an inadequate dose has been administered or when anti-D immunoglobulin prophylaxis is omitted following a sensitising event.5,6 Postpartum doses may be omitted due to oversight or loss to follow-up. Sensitisation may occur spontaneously during the first pregnancy without any identifiable event causing feto-maternal haemorrhage. Inadequate dosing can be avoided by application of the Kleihauer test to estimate the size of any transplacental haemorrhage.1
Significant feto-maternal transfusion may also occur following still-birth, abortion (both therapeutic and spontaneous), threatened abortion, external fetal version, abdominal injury, or amniocentesis.
The efficacy of postpartum prophylaxis is not in question but opinions differ on the need for prophylaxis during pregnancy. It is generally agreed that prophylaxis is necessary following therapeutic terminations at any stage of pregnancy,7,8 including medical termination utilising mifepristone,9 but there is no generally accepted policy for other possibly sensitising events. A study of 655 Rh(D)-negative women in Denmark,10 where antepartum prophylaxis is not common practice, suggested that the sensitisation rate following amniocentesis was no higher than the spontaneous sensitisation rate. Surveys of general medical practitioners and consultant obstetricians and haematologists in the UK11,12 have suggested that many do not recommend routine prophylaxis following early complete or threatened miscarriages; 74% of general practitioners in one survey12 never gave anti-D immunoglobulin after threatened miscarriages. Spontaneous miscarriages during early pregnancy might not cause sensitisation so long as there is no surgical intervention.7,8,13 Nonetheless, the Royal College of Obstetricians and Gynaecologists and other authorities in the UK urge routine antenatal prophylaxis for all Rh(D)-negative women. Others14,15 represent the alternative opinion that, with the shortage of anti-D immunoglobulin, indiscriminate use should be avoided14 and attention should be focussed upon administration of adequate doses following term deliveries and terminations of pregnancy in Rh(D)-negative women.5,15
Further debate arises over the significance of spontaneous sensitisation during the first pregnancy. In one study,16 administration of anti-D immunoglobulin to 2069 Rh(D)-negative primigravidas at 28 and 34 weeks as well as standard postpartum administration was more effective at preventing immunisation than standard postpartum prophylaxis in 2000 primigravidas. In a subsequent analysis of women from this study17 following further pregnancies, comparison with a group of Rh(D)-positive mothers showed no detrimental effects to mothers or infants. In addition, antenatal prophylaxis may not need to be given beyond the first pregnancy. Nevertheless, concerns have been expressed18 over the consequent unnecessary administration of anti-D immunoglobulin to women who are carrying Rh(D)-negative fetuses and the possible long-term effects, although anti-D immunoglobulin has had a good safety record.19 Both factions agree18,20 on the desirability of identifying high-risk women to reduce the indiscriminate use of anti-D immunoglobulin. A remaining major stumbling block, in the UK at least, is the continuing expense and scarcity of anti-D immunoglobulin. Supplies are derived from plasma collected from Rh-negative donors who have to undergo potentially hazardous sensitisation with Rh-positive red blood cells. The development of genetically-engineered anti-D immunoglobulin should help to improve availability. The UK3 and WHO2 guidelines may represent a counsel of perfection, but until difficulties with supply are overcome, prophylaxis during the first pregnancy for Rh(D)-negative women, thus ensuring the possibility of two unaffected infants, would seem a reasonable priority.
Treatment. In mild cases, the resultant hyperbilirubinaemia can be managed with phototherapy. In severe cases, exchange transfusions may be necessary and intra-uterine transfusions may be considered in pregnancies of less than about 34 weeks’ gestation; beyond this, premature delivery is often preferable.21 Some clinicians22 have reported treatment failures with intra-uterine transfusions but have found the intravenous administration of normal immunoglobulin 400 mg/kg daily for 5 days every 2 to 3 weeks to the mother to be effective. There are several case reports23,24 of beneficial responses using similar doses, but no benefit was seen in 4 patients receiving 1000 mg/kg once a week.25 This dose, however, appeared to reduce the severity of the disease in a patient with Kell sensitisation.25 Reductions in bilirubin concentrations have been reported following intravenous administration of normal immunoglobulin 500 mg/kg as a single dose to newborn infants.26 Preliminary studies in small numbers of infants27,28 suggest that epoetins may be of value in controlling anaemia which develops 2 to 8 weeks after birth.
For further information on the substances mentioned above, see:
- Anti-D Immunoglobulins,
- Normal Immunoglobulins,
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