Effectiveness of Antenatal Anti-D Prophylaxis Figure 4. Impact of adjusting for bias in the meta-analysis of 10 studies comparing RAADP to control. (a) unadjusted odds ratios (with 95% CIs); (b) odds ratios adjusted for internal biases (with 95% CIs); (c) odds ratios adjusted for all biases (with 95% CIs). doi:10.1371/journal.pone.0030711.g004 for internal biases, the pooled odds ratio for sensitisation was estimated as 0.28 (95% CI 0.15, 0.53), comparing RAADP to control, and there was no remaining evidence of between-study heterogeneity (I2 = 0%). This result allows for the methodological limitations in the RAADP studies, but does not acknowledge their varying relevance to the target setting of interest to NICE. As a sensitivity analysis, we also present results from a meta- analysis excluding the Bowman (2) and Bowman (3) studies [7,8], which share a control group with Bowman (1) [6]. In a bias- adjusted meta-analysis of these 8 studies, the pooled odds ratio for sensitisation was estimated as 0.31 (95% CI 0.16, 0.61), with no evidence of heterogeneity (I2 = 0%). The numerical result is similar to that based on all 10 studies and the conclusions from the analysis are unchanged. To check the robustness of our findings, we also performed separate meta-analyses using the opinions of each assessor in turn. The results obtained from adjusting for the opinions of each internal bias assessor were similar to each other and close to results adjusted for pooled opinion on internal bias. Meta-analyses adjusted for each external bias assessor in turn (following adjustment for pooled opinion on internal bias) were also similar to each other and close to the pooled bias-adjusted meta-analysis. Analysis comparing different dose regimens In a meta-regression analysis, we estimated the association between the observed results for each anti-D dose in the studies available and the pooled opinion on a measure of relative effectiveness of each dose (Figure 5). Within this analysis, we predicted the underlying odds ratios we would expect for each of the three licensed anti-D treatments, in a new study evaluating their effectiveness compared to control (without allowance for sampling variation). The estimated odds ratios for sensitisation are 0.31 (95% CI 0.09, 0.65) for a dose of 500 IU at 28 and 34 weeks, 0.42 (95% CI 0.17, 0.73) for a dose of 1500 IU at 28–30 weeks, and 0.18 (95% CI 0.03, 0.53) for a dose of 1250 IU at 28 and 34 weeks. Using the data available for other doses of anti-D and the beliefs on relative effectiveness elicited from four assessors, we have estimated odds ratios for the effectiveness of two licensed treatments which have not yet been evaluated. Each of the two unevaluated treatments is expected to be effective for prevention of sensitisation. Among the three licensed treatments, the estimated probability that a dose of 1250 IU at 28 and 34 weeks is most effective is 83%, while the probability that a dose of 500 IU at 28 and 34 weeks is most effective is 15%. The probability that a single dose of 1500 IU at 28–30 weeks is least effective amongst these three regimens is estimated as 76%. Discussion A bias-adjusted meta-analysis allowed us to synthesise all available evidence on the effectiveness of RAADP, while adjusting for differences in study quality and design. The pooled bias- adjusted results presented here provide strong evidence that RAADP prevents sensitisation in pregnant Rhesus negative women. These findings confirm the conclusions of the two NICE appraisals, which did not include a quantitative synthesis of all evidence. It is reassuring to find that, when all evidence on clinical effectiveness is taken into account, the widespread policy of PLoS ONE | www.plosone.org 8 February 2012 | Volume 7 | Issue 2 | e30711