Rhogam: A Lifesaving Breakthrough

In general hospital, pregnancies where the mother has RhD negative blood is 14% (Izebetgovic, 2013). All pregnant women with RhD negative blood present with risk for hemolytic disease of the newborn (HDN) and that risk increases with each consecutive pregnancy (Antonios, 2011). HDN in severe cases results in fetal death. Anti-RhD antibody, better known as ‘RhoGam’, was made available in 1968 as a treatment for HDN and reduced the number of cases of RhD negative pregnant women presenting with HDN from 18% to less than 1% (Izebetgovic, 2013).

History

HDN was described in 1609 in France (Izetbegovic, 2013). The first medical case was in 1939 with two physicians, Levine and Stetson, reporting abnormal blood clotting postpartum which they contributed to unknown antibodies and an antigen. In 1940, Landsteiner and Wiener coined the name Rh-factor to describe the antigen which they initially believed was also present on Rhesus monkey red blood cells (Antonios, 2011). In the late 1950’s research increased and a British Scientist proposed that anti-RhD antibodies could be used to prevent the presentation of HDN. Researchers from Ortho Pharmaceutical and Columbian Presbyterian Medical Center designed a study to prove the efficacy of the idea. Male inmates were injected with RhD antibodies and then exposed to RhD antigen. The study results showed overwhelmingly that injected RhD antibody prevented the formation of an immune response to the RhD antigen. RhD antibodies in injectable form were approved and made available in 1968 (Clark, 2012).

Hemolytic Disease

Hemolytic disease of the newborn (HDN) involves IgG antibodies against RhD, a RBC surface protein, crossing the placental barrier and attacking the fetal RBC supply. Immune system initiated RBC destruction results in fetal jaundice, anemia, enlarged organs, edema, hydrops (fluid throughout body tissue), and, if severe, cardiac and respiratory failure (Medline Plus, 2018). As noted above, roughly 14% of the United States population is at risk for developing HDN and both the risk and severity increase with repeated pregnancy.

RhoGam Mechanism of Action (MOA)

Research has been unable to answer, in entirety, why RhoGam is effective at preventing the activation of maternal humoral response and HDN. Current hypotheses discuss the likelihood that injected circulating anti-RhD antibodies (RhoGam) bind fetal RBC’s resulting in cell lysis and destruction before antigen presenting cells and maternal humoral immunity are activated. Preventing activation of maternal humoral immunity eliminates the high numbers of anti-RhD antibody that are capable of causing HDN. This theory is supported by the finding that RhoGam treatment is effective in preventing the activation of humoral immunity against RBC antigens other than the RhD antigen (Zwiers et al, 2018).

Potential Side Effects

Of interest is the reality that RhoGam anti-RhD antibodies are capable of crossing the placenta in the same way that maternal humoral responses of IgG can. It follows that a potential risk of RhoGam treatment is RhoGam induced HDN. A positive DAT (testing for the presence of any anti-RhD antibodies on fetal RBC’s) varies from 2 to 30% in women treated with RhoGam. Positive DAT testing is often seen in women receiving 2 or more RhoGam shots antenatally, a practice currently uncommon (Sabramynian & Pereira, 2016). Maayan-Metzger et al in their retrospective analysis concluded that there was not a significant risk to neonates whose mothers had been treated with anti-RhD antibody (Maaya-Metzger et al, 2001). The effectiveness of RhoGam treatment should be weighed against risk with Sabramynian and Pereira reporting a decrease of HDN from 13-14% to less than 0.1% when Rhogam treatments are used (Sabramynian & Pereira, 2016).

Treatment

Typical treatment with RhoGam involves an intramuscular injection at week 28 of pregnancy and one injection postpartum. The average cost is around $200 per injection. While rare, there can be serious allergic responses to IgG antibodies. Typical side effects include soreness and some swelling at the injection site.

References

Antonios, Nathalie. (2011). Rh incompatibility in pregnancy. The Embryo Project Encyclopedia, Retrieved from: https://embryo.asu.edu/pages/rh-incompatibility-pregnancy

Clark, Camille. (2012). Rhogam: the triumph of medical science over rh disease. Obstetric and Gynocology, PA. Retrieved from: https://www.dallasobgynpa.com/articles/entryid/171/rhogam-the-triumph-of-medical-science-over-rh-disease

Izebetgovic,, Sebija. (2013). Occurrence of ABO and RhD incompatibility with Rh negative mothers. Mater Siciomed, 25(4): 255-258. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914752/

Maayan-Metzger, A., Schwartz, T., Sulkes, L., Marlob, P. (2001). Maternal anti-D prophylaxis during pregnancy does not cause neonatal haemolysis. Arch Dis Child Fetal Neonatal Ed., 84(1): 60-62.

Medline Plus. (2018). Hemolytic disease of the newborn. U.S. National Library of Medicine. Retrieved from: https://medlineplus.gov/ency/article/001298.html

Sabramynian, Rajeswar., Pereira, Karishma. (2016). Is antenatal RhIg completely safe? Rev Bras Hematol Hemoter, 38(2): 161-162. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877609/

Zwiers, C., Koelewijn, JM., Vermij, L., Sambeeck, V., Oapkes, D., M, de Hass., Schoot, Van der. (2018). ABO incompatibility and RhIG immunoprophylaxis prevent against non-D alloimmunization by pregnancy. NCBI Transfusion, 58(7): 1611-1617. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/29624682