The scientific basis of antenatal prophylaxis

Background Standard post-delivery administration of anti-D, together with f urther 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 re asons: i) failure to administer sufficient anti-D at the correct time after known at-risk events, either during pregnancy or at delivery; and ii) allo immunisation 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 intra partum alloimmunisation as being the 'true' cause of alloimmunisation is be st assessed by studying first pregnancies, and rigorous analysis of antenat al anti-D efficacy should preferably include observation in second pregnanc ies to avoid underestimation of alloimmunisation. Ideally there should be n o exclusions, i.e. treating both arms of the study on an 'intention to trea t' basis, otherwise there will be an overestimate of efficacy under routine practice conditions. Initial safety concerns about effects of antenatal an ti-D on the fetus have not been confirmed in practice. Options Although there is only one randomised controlled clinical trial (wi th small numbers) demonstrating a further reduction in alloimmunisation fol lowing antenatal administration of anti-D-1 meriting a grade A recommendati on (see appendix II). the total body of evidence of efficiency is compellin g. Whilst two doses of 300 mu g are effective, this is no more so than the single dose in practice, and as it requires considerably more anti-D immuno globulin, it is probably not cost effective. Lf a single dose is to be give n, it is too late at 34 weeks, and 28 weeks is to be recommended. If divide d doses are to be given at 28 and 34 weeks, 50 mu g is insufficient, and 10 0 mu g is recommended. Two dose regimes can be recommended, as follows: i) single dose of 300 mu g at 28 weeks - the results of the single 360 mu g dose in first pregnancies is limited to the Canadian study(2) with observe d reduction from 1.6% (45/2768) in concurrent nonrandomised controls to 0.1 8% (2/1086) in the treatment group. ii) two doses of 100 mu g at 28 and 34 weeks - the two controlled studies g ive similar results in first pregnancies(3,4). A reduction in alloimmunisat ion is seen from 1.11% (4/360) in controls to <0.28% (0/362) in the treatme nt group in the French study(3), and from 0.95% (19/2000) in controls to 0. 32% (4/1238) in the treatment group in the English study(4). Whilst anti-D is in limited supply, it is more cost effective to restrict a ntenatal prophylaxis to first pregnancies. It is also probable that a singl e dose of 250 mu g (as used in Europe) will be as effective in practice as the 300 mu g dose, given the limitations of the anti-D quantification assay and the vial overfill introduced by manufacturers, but this has not been f ormally proven in clinical trials. The number of RhD deaths is now very low , even with standard postpartum prophylaxis, but there is a systematic unde rreporting in the UK, due to early fetal deaths being recorded as 'abortion ' rather than as haemolytic disease of the newborn (HDN). There have been n o systematic studies on the reduction in mortality observed with antepartum anti-D. Nevertheless, it is self-evident that if immunisation is largely p revented, then so will fetal morbidity and mortality.