Monoclonal RhD prophylaxis: high time to evaluate efficacy
Authors: EJT Verweij, Abera Kenay Tura, Tadesse Gure, Jeremia Pyuza, Bariki Mchome, Kondwani Kawaza, Peter Moons, Derek de Winter, Renske van't Oever, Steven Spitalnik, C Ellen van der Schoot, Thomas van den Akker
Journal: The Lancet (2024)

Rhesus disease, a form of haemolytic disease of the fetus and newborn (HDFN), occurs when the immune system of a pregnant woman responds to red blood cells of her unborn child. This response can happen when a pregnant woman and her fetus have different blood types. If left untreated, HDFN can result in severe anaemia, jaundice, and even severe brain damage (ie, kernicterus) and death. Since the 1960s, screening for the RhD blood group antigen and the administration of rhesus immunoprophylaxis (RhIG) to RhD-negative pregnant women has substantially decreased rhesus disease in high-income countries. Before the introduction of this immunoprophylaxis, 17–20% of RhD-negative pregnant women became immunised, which dropped to around 0·5% with postnatal RhIg prophylaxis1Pollack W Gorman JG Freda VJ Ascari WQ Allen AE Baker WJ Results of clinical trials of RhoGAM in women.Transfusion. 1968; 8: 151-153Crossref PubMed Scopus (80) Google Scholar, 2Koelewijn JM de Haas M Vrijkotte TG Bonsel GJ van der Schoot CE One single dose of 100 microg of antenatal RhIG halves the risk of anti-D immunization and hemolytic disease of the fetus and newborn in the next pregnancy.Transfusion. 2008; 48: 1721-1729Crossref PubMed Scopus (77) Google Scholar and decreased even further after adding antenatal prophylaxis.2Koelewijn JM de Haas M Vrijkotte TG Bonsel GJ van der Schoot CE One single dose of 100 microg of antenatal RhIG halves the risk of anti-D immunization and hemolytic disease of the fetus and newborn in the next pregnancy.Transfusion. 2008; 48: 1721-1729Crossref PubMed Scopus (77) Google Scholar Contrastingly, the clinical burden of HDFN in low-income and middle-income countries remains high.3Visser GHA Thommesen T Di Renzo GC Nassar AH Spitalnik SL FIGO/ICM guidelines for preventing rhesus disease: a call to action.Int J Gynaecol Obstet. 2021; 152: 144-147Crossref Scopus (19) Google Scholar The International Federation of Gynecology and Obstetrics (FIGO) and the Worldwide Initiative for Rh-Disease Eradication (WIRhE) estimate that HDFN continues to result in more than 160 000 perinatal deaths and 100 000 disabilities annually.3Visser GHA Thommesen T Di Renzo GC Nassar AH Spitalnik SL FIGO/ICM guidelines for preventing rhesus disease: a call to action.Int J Gynaecol Obstet. 2021; 152: 144-147Crossref Scopus (19) Google Scholar Specifically, the burden of HDFN in sub-Saharan Africa is unknown because of the absence of population-based data, but is likely to be considerable.3Visser GHA Thommesen T Di Renzo GC Nassar AH Spitalnik SL FIGO/ICM guidelines for preventing rhesus disease: a call to action.Int J Gynaecol Obstet. 2021; 152: 144-147Crossref Scopus (19) Google Scholar A call to action by the FIGO and WIRhE has been answered by several initiatives, including our AFRICARhE project, which aims to eradicate HDFN from the African continent. During the start-up phase, we learned that a monoclonal RhIG, produced by a mouse–human heterohybridoma cell line (ie, Rhoclone; Bharat Serums and Vaccines, Navi Mumbai, India) is available at a large scale in several African countries, although its efficacy has not been robustly studied. For many working on HDFN in high-income settings over many years, this finding was eye opening. Only two clinical trials of 110 women4Chauhan AR Bhattacharyya MS Turakhia N Daftary GV Efficacy and safety of monoclonal anti-D immunoglobulin in comparison with polyclonal anti-D immunoglobulin in prevention of rho isoimmunization.J Assoc Physicians India. 2002; 50: 1341-1342PubMed Google Scholar and 105 women5Chauhan AR Nandanwar YS Ramaiah A et al.A multicenter, randomized, open-label trial comparing the efficacy and safety of monoclonal anti-Rh (D) immunoglobulin with polyclonal anti-Rh(D) immunoglobulin for the prevention of maternal Rh-isoimmunization.J Obstet Gynecol India. 2019; 69: 420-425Crossref Scopus (6) Google Scholar receiving postpartum Rhoclone were reported in the international literature. Although no alloimmune sensitisation was seen in the total of 186 women across these two trials who were not lost to follow-up and were treated with monoclonal RhIg and tested at day 90 postpartum, day 180 postpartum, or both, there were no data provided regarding parity or fetal–maternal ABO compatibility. In addition, because the pre-existing presence of maternal anti-D antibodies was an appropriate exclusion criterion, non-responders to blood group alloimmunisation might have been preferentially recruited. Finally, no follow-up concerning subsequent pregnancies was reported, which is particularly relevant because primary immunisation to RhD might only be recognised after a secondary immune response.6Contreras M Kumpel B Olovnikova N Anti-RhD immunoglobulin for the prevention of hemolytic disease of the fetus and newborn: polyclonal versus monoclonal antibodies.https://www.glowm.com/article/id/418843#Date: January, 2023Date accessed: July 14, 2023Google Scholar In high-income countries, only polyclonal RhIG is used to prevent HDFN; in the USA, RhIG is mostly prepared with plasma from hyperimmunised male donors. Although this immunoprophylaxis is highly effective, the supply of RhIg is not sufficient to meet the needs of all women at risk worldwide. This global shortage of RhIG was exacerbated by the COVID-19 pandemic, which caused delays in donor recruitment. Therefore, an unlimited supply of monoclonal RhIG would be ideal. Attempts to produce monoclonal RhIG and robustly establish therapeutic efficacy have been unsuccessful for various reasons, including insufficient funding for phase 3 trials.6Contreras M Kumpel B Olovnikova N Anti-RhD immunoglobulin for the prevention of hemolytic disease of the fetus and newborn: polyclonal versus monoclonal antibodies.https://www.glowm.com/article/id/418843#Date: January, 2023Date accessed: July 14, 2023Google Scholar Moreover, the lack of mechanistic understanding of this type of immunoprophylaxis, the absence of an RhD animal model, and the observation that some monoclonal antibodies might even increase alloimmunisation risk have hampered the development of monoclonal RhIG. Ethical considerations might also have had a role because conducting a clinical trial in which a highly effective polyclonal RhIG is withheld from pregnant women in need is difficult. In summary, although preliminary findings suggest that monoclonal RhIG might be a useful alternative to polyclonal RhIG, we believe that more extensive and rigorous trials are necessary to establish its efficacy. Nonetheless, given that monoclonal RhIG is currently administered in several countries, its effectiveness can be studied in postmarketing (ie, phase 4) observational studies without ethical challenge. In addition, even if monoclonal RhIG efficacy is shown in a retrospective series, advancing a randomised controlled trial comparing the efficacy of monoclonal and polyclonal RhIG would still be crucial. Such a trial should first be performed in a setting with access to antenatal treatment, including intrauterine transfusion for severe HDFN, in case prophylaxis fails. We declare no competing interests. AFRICARhE has been in contact with Kedrion about potential sponsorship of RhIg (D) immunoprophylaxis for the project in Ethiopia, Malawi, and Tanzania. No official agreements have been made. Attempts to have contact with Bharat Serums and Vaccines have not been successful, but ongoing efforts will be made. Members of the AFRICARhE consortium are listed in the appendix Download .pdf (.12 MB) Help with pdf files Supplementary appendix