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Rh immune globulin (RhIG) is a medication that contains antibodies to Rh antigen D (RhD), which may be present on the surface of red blood cells (RBCs) in some individuals. It prevents a person’s immune system from recognizing RhD, thus suppressing a potentially fatal immune reaction. 

RhIG has been in use since the late 1960s and is listed in the World Health Organization's List of Essential Medicines as being safe and effective. However, it also has a range of common side effects that include hemolysis, fever, headaches and pain at the injection site. Fortunately, RHD genotyping helps standardize RhIG administration while also reducing unnecessary use of the drug, which carries ethical implications for the healthcare provider.

Below, we explore these benefits while also providing a brief history of RhIG. 


An expectant mother is at risk of RhD alloimmunization if she is RhD-negative and her fetus is RhD-positive. The mother’s body may mount an immune response to the fetal RBCs by developing RhD antibodies, which usually has little impact on the first pregnancy. However, these antibodies place subsequent pregnancies with an RhD-positive fetus at significant risk of hemolytic disease of the fetus and newborn (HDFN), which can be fatal to the fetus. 

The American College of Obstetricians and Gynecologists (ACOG) reports that about one out of seven fetuses affected by this condition are stillborn, and half of live births result in brain injury and neonatal death. The ACOG therefore recommends that all RhD-negative expectant mothers receive RhIG treatment at about the 28th week of pregnancy and again shortly after delivery.


The first report on RhD, initially named Du, was published in 1946. The first edition of the American Association of Blood Banks AABB Standards was published in 1958, which required testing by direct agglutination with anti-D typing serum to determine the donor’s RhD type. Donors with a weakly positive result for RhD were considered RhD-positive.

The 10th edition of the AABB Standards published in 1981 changed RhD typing practices in the United States. This edition recommended RhD typing for the purpose of RhIG treatment by using the same methods that was already in place for blood donors. However, pregnant women and transfusion recipients with a weakly positive RhD result were considered RhD-negative.

ACOG guidance remained unchanged on the issue of the serologic weak D phenotype in 1999, although Sandler et al. reports that some laboratories no longer classified pregnant women with this phenotype as Rh-negative. However, the 22nd edition of Standards published in 2003 didn't require a test for weak D if the woman’s test for RhD was negative. This is still the case as of the 29th edition of Standards published in 2014.

The strategy of interpreting a serologic weak D phenotype as RhD-positive for blood donors and RhD-negative for obstetrics patients has remained the standard practice for over 50 years. The 29th edition of the AABB Standards does require a method of typing blood with a weak expression of RhD for blood donors, but generally considers it unnecessary for RhIG treatment. The sole exception to this recommendation is cases where an expectant mother is RhD-negative.

Ethical Implications

RhIG has greatly reduced the risk of HDFN, but its unnecessary use has ethical implications. First, RhIG is derived from RhD-negative donors, who must be alloimmunized. This process increases their health risk if they need a blood transfusion and RhD-negative blood isn’t available. Another concern is that human-derived products should be reserved for patients who really need it, which makes intentional alloimmunization even more ethically questionable. Finally, the cost of manufacturing and administering RhIG to patients who don’t need it places a financial burden on them, according to Kacker et al.

RHD Genotyping

RHD genotyping can eliminate the need for administering RhIG unnecessarily by accurately classifying serologic weak D phenotypes. It’s a one-time test that can identify patients with Weak D Types 1, 2 or 3, allowing practitioners to safely manage them as RhD-positive. Patients with this classification don’t require RhIG treatment during any pregnancy or when receiving blood. Furthermore, RHD genotyping also correctly identifies patients with other RHD variants besides Weak D Types 1, 2 or 3—such as partial D—and helps providers more accurately deliver RhIG to groups at risk of clinically significant sensitization. 

For more on RHD genotyping and the benefits of phasing it in at your practice, download a free copy of “It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype” by Sandler et al., 2015 here.