Effectiveness of Antenatal Anti-D Prophylaxis Figure 5. Exploratory analysis comparing different dose regimens. For each of seven RAADP treatment regimens: elicited relative effectiveness compared to an optimally effective treatment (67% intervals pooled across assessors); observed odds ratios comparing RAADP to control (with 95% intervals), where available; and odds ratios expected in a future study comparing RAADP to control (with 95% intervals), obtained from a fitted meta-regression model. (Higher values for relative effectiveness compared to an optimal treatment correspond to lower odds ratios compared to control.). doi:10.1371/journal.pone.0030711.g005 offering RAADP to all non-sensitised pregnant Rhesus negative women remains strongly supported. However, the cost-effective- ness of this policy should also be reconsidered. Since the bias- adjusted meta-analysis of 10 studies produces a larger treatment effect estimate (and 95% interval further from the value) than the meta-analysis of two studies used in cost-effectiveness modelling in the NICE appraisals, it is very likely that RAADP would again be judged cost-effective on the basis of the new results. Two of the licensed anti-D treatments have not yet been evaluated. In a meta-regression analysis, we predicted the underlying effectiveness odds ratios that we would expect for these treatments if they were compared against control antenatal care in a future trial. In the absence of a head-to-head trial comparing the three licensed treatments directly, this provides useful information on their expected relative effectiveness. Our model gave a high probability that a dose of 1250 IU at 28 and 34 weeks would be the most effective amongst the three licensed treatments, and a high probability that a single dose of 1500 IU at 28–30 weeks would be the least effective. These results could inform an economic model to compare the expected cost- effectiveness of the three licensed treatments and determine which is the optimum dose regimen of RAADP. However, a large randomised trial comparing the three licensed doses would provide much firmer evidence on their relative clinical effective- ness and cost-effectiveness. When comparing the licensed regimens, we have not taken into account ethical considerations. Some women are reluctant to receive blood products and their reluctance may be greater for a two-dose regimen using larger doses of immunoglobulin. If problems with availability of anti-D immunoglobulin are encoun- tered in the future, a regimen which minimises the total volume of plasma administered would be preferred. New technologies currently under development could potentially lead to consider- able changes in the antenatal care of Rhesus negative women. Recombinant anti -D immunoglobulin is expected to become available and would provide a safer, more acceptable alternative to human plasma immunoglobulin. In addition, if antenatal fetal genotyping becomes widespread and cost-effective, this would allow targeted antenatal anti-D prophylaxis in pregnancies where the fetus is found to be Rhesus positive [23]. Without adjustment for variations in study design and quality, it would be inappropriate to combine evidence from all available RAADP studies. In comparison with the unadjusted meta-analysis, the weights given to the studies in calculation of the pooled result changed considerably after adjustment for biases. In particular, the weights given to the higher quality studies (MacKenzie [12], Mayne [13] and Huchet [10]) were increased, while the influence of lower quality studies was reduced. By adjusting for bias and acknowledging uncertainty over its impact, we aimed to remove unexplained between-study heterogeneity from the meta-analysis [19], and this was achieved in the analysis of the RAADP studies. The bias-adjustment process relies on incorporating expert opinion. Subjective judgement is routinely used in meta-analysis. The standard approach to handling studies of diverse quality and design is to choose a minimum threshold for inclusion and regard those studies included as unbiased. By presenting results from both unadjusted and bias-adjusted meta-analyses, as in this paper, subjective opinion is made transparent and accountable. The experts who quantified the biases were carefully chosen for their knowledge of anti-D prophylaxis (or their quantitative expertise, for internal biases), and their opinions were combined in such a way that no individual view could overly influence the final results of the meta-analysis. Conclusion A bias-adjusted synthesis of all available evidence provides strong evidence for the effectiveness of RAADP in preventing sensitisation, in support of the policy of offering RAADP to all non-sensitised pregnant Rhesus negative women. All three licensed PLoS ONE | www.plosone.org 9 February 2012 | Volume 7 | Issue 2 | e30711