The scientific basis of antenatal prophylaxis



Background Standard post-delivery administration of anti-D, together with further anti-D for events known to result in fetomaternal haemorrhage (FMH) during pregnancy, has reduced the incidence of alloimmunisation in RhD women to 0.83—1.5% in the UK. Residual alloimmunisation occurs mainly for two reasons: i) failure to administer sufficient anti-D at the correct time after known at-risk events, either during pregnancy or at delivery; and ii) alloimmunisation during pregnancy as a result of ‘silent’ FMH. The RhD antigen is well developed by 6 weeks’ gestation and the fetoplacental blood volume increases during pregnancy. Studies show that 3% of pregnant women have FMH in the first trimester, 12% in the second, and 45% in the third. Analysis of alloimmunisation in primigravidae clearly shows that on average, 90% are detectable after 28 weeks’ gestation. Additional anti-D prophylaxis during the course of pregnancy, starting at 28 weeks, can reduce alloimmunisation to a minimum by protecting against occult FMH. The identification of intrapartum alloimmunisation as being the ‘true’ cause of alloimmunisation is best assessed by studying first pregnancies, and rigorous analysis of antenatal anti-D efficacy should preferably include observation in second pregnancies to avoid underestimation of alloimmunisation. Ideally there should be no exclusions, i.e. treating both arms of the study on an ‘intention to treat’ basis, otherwise there will be an overestimate of efficacy under routine practice conditions. Initial safety concerns about effects of antenatal anti-D on the fetus have not been confirmed in practice.

Options Although there is only one randomised controlled clinical trial (with small numbers) demonstrating a further reduction in alloimmunisation following antenatal administration of anti-D1 meriting a grade A recommendation (see appendix II), the total body of evidence of efficiency is compelling. Whilst two doses of 300μg are effective, this is no more so than the single dose in practice, and as it requires considerably more anti-D immunoglobulin, it is probably not cost effective. If a single dose is to be given, it is too late at 34 weeks, and 28 weeks is to be recommended. If divided doses are to be given at 28 and 34 weeks, 50μg is insufficient, and 100 μg is recommended. Two dose regimes can be recommended, as follows:

  • i) single dose of 300μg at 28 weeks the results of the single 300pg dose in first pregnancies is limited to the Canadian study2 with observed reduction from 1.6% (45/2768) in concurrent nonrandomised controls to 0.18% (2/1086) in the treatment group.
  • ii) two doses of 100μg at 28 and 34 weeks—the two controlled studies give similar results in first pregnancies3,4. A reduction in alloimmunisation is seen from 1.11 % (4/360) in controls to <0.28% (0/362) in the treatment group in the French study3, and from 0.95% (19/2000) in controls to 0.32% (4/1238) in the treatment group in the English study4.

Whilst anti-D is in limited supply, it is more cost effective to restrict antenatal prophylaxis to first pregnancies. It is also probable that a single dose of 250μg (as used in Europe) will be as effective in practice as the 300μg dose, given the limitations of the anti-D quantification assay, and the vial overfill introduced by manufacturers, but this has not been formally proven in clinical trials. The number of RhD deaths is now very low, even with standard postpartum prophylaxis, but there is a systematic underreporting in the UK, due to early fetal deaths being recorded as ‘abortion’ rather than as haemolytic disease of the newborn (HDN). There have been no systematic studies on the reduction in mortality observed with antepartum anti-D. Nevertheless, it is self-evident that if immunisation is largely prevented, then so will fetal morbidity and mortality.