Routine Antenatal Anti-D Prophylaxis in Women Who Are Rh(D) Negative: Meta-Analyses Adjusted for Differences in Study Design and Quality Rebecca M. Turner1*, Myfanwy Lloyd-Jones2, Dilly O. C. Anumba3, Gordon C. S. Smith4, David J. Spiegelhalter1,5, Hazel Squires2, John W. Stevens6, Michael J. Sweeting1, Stanislaw J. Urbaniak7, Robert Webster8, Simon G. Thompson9 1 Medical Research Council Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom, 2 Health Economics and Decision Science, University of Sheffield, Sheffield, United Kingdom, 3 Academic Unit of Reproductive and Developmental Medicine, The University of Sheffield Medical School, Sheffield, United Kingdom, 4 Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United Kingdom, 5 Statistical Laboratory, University of Cambridge, Cambridge, United Kingdom, 6 Centre for Bayesian Statistics in Health Economics, University of Sheffield, Sheffield, United Kingdom, 7 Academic Transfusion Medicine Unit, University of Aberdeen, Foresterhill, United Kingdom, 8 National Blood Service Sheffield Centre, National Health Service Blood and Transplant, Sheffield, United Kingdom, 9 Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom Abstract Background: To estimate the effectiveness of routine antenatal anti-D prophylaxis for preventing sensitisation in pregnant Rhesus negative women, and to explore whether this depends on the treatment regimen adopted. Methods: Ten studies identified in a previous systematic literature search were included. Potential sources of bias were systematically identified using bias checklists, and their impact and uncertainty were quantified using expert opinion. Study results were adjusted for biases and combined, first in a random-effects meta-analysis and then in a random-effects meta- regression analysis. Results: In a conventional meta-analysis, the pooled odds ratio for sensitisation was estimated as 0.25 (95% CI 0.18, 0.36), comparing routine antenatal anti-D prophylaxis to control, with some heterogeneity (I2 = 19%). However, this na¨ıve analysis ignores substantial differences in study quality and design. After adjusting for these, the pooled odds ratio for sensitisation was estimated as 0.31 (95% CI 0.17, 0.56), with no evidence of heterogeneity (I2 = 0%). A meta-regression analysis was performed, which used the data available from the ten anti-D prophylaxis studies to inform us about the relative effectiveness of three licensed treatments. This gave an 83% probability that a dose of 1250 IU at 28 and 34 weeks is most effective and a 76% probability that a single dose of 1500 IU at 28–30 weeks is least effective. Conclusion: There is strong evidence for the effectiveness of routine antenatal anti-D prophylaxis for prevention of sensitisation, in support of the policy of offering routine prophylaxis to all non-sensitised pregnant Rhesus negative women. All three licensed dose regimens are expected to be effective. Citation: Turner RM, Lloyd-Jones M, Anumba DOC, Smith GCS, Spiegelhalter DJ, et al. (2012) Routine Antenatal Anti-D Prophylaxis in Women Who Are Rh(D) Negative: Meta-Analyses Adjusted for Differences in Study Design and Quality. PLoS ONE 7(2): e30711. doi:10.1371/journal.pone.0030711 Editor: Dimas Tadeu Covas, University of Sao Paulo – USP, Brazil Received July 28, 2011; Accepted December 27, 2011; Published February 3, 2012 Copyright: 2012 Turner et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: RT, DS, MS and ST were supported by the United Kingdom Medical Research Council grants U.1052.00.001, U.1052.00.011 and U.1052.00.005. MLJ and HS were supported by grants awarded by the National Institute on Health Research (NIHR) Health Technology Assessment Programme. GS was supported by the NIHR Cambridge Comprehensive Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: HS led the NICE appraisal of antenatal anti-D prophylaxis published in 2009. MLJ co-authored the NICE appraisals published in 2003 and 2009. RW is employed by the United Kingdom National Health Service Blood and Transplant. The other authors declare no competing interests. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: rebecca.turner@mrc-bsu.cam.ac.uk Introduction Women who are Rhesus negative require particular antenatal care and monitoring during pregnancy. If the fetus carried is Rhesus positive, there is a risk that mixing of fetal and maternal blood cells will lead to the woman becoming sensitised, which may cause fetuses in any subsequent pregnancies to suffer from haemolytic disease of the newborn [1]. Women in developed countries have long been offered targeted anti-D immunoglobulin with the aim of preventing sensitisation, after the birth of a Rhesus positive baby and after other potentially sensitising events such as miscarriage, termination of pregnancy or amniocentesis [2]. Under this policy, the incidence of haemolytic disease of the newborn was substantially reduced but was still believed to cause death in 6 out of 100 000 live births [3]. The UK National Institute for Health and Clinical Excellence (NICE) evaluated, first in 2003 and subsequently updated in 2009, the potential benefits from offering routine antenatal anti-D prophylaxis (RAADP) to all PLoS ONE | www.plosone.org 1 February 2012 | Volume 7 | Issue 2 | e30711