Download and read the Sandler et al. study 

Unlike other blood group antigens—such as ABO—that serologic testing detects as either positive or negative, RhD antigen testing can be equivocal due to variant RHD genes that lead to multiple phenotypes including weak D, partial D and DEL phenotypes. For clinical management of obstetrics patients, in particular, it is important to classify these diverse RhD phenotypes correctly to avoid the effects of RhD alloimmunization and erythroblastosis fetalis.

Particularly for serologic weak D phenotypes, there have been inconsistencies in the standard protocols for reporting these results. A serologic weak D phenotype is defined as reactivity of red blood cells (RBCs) with anti-D antibody showing weak (<=2+) or no reactivity initially, but agglutinating moderately or strongly with the addition of antihuman globulin. Different laboratories may report a patient with a serologic weak D phenotype as either RhD-positive or RhD-negative, leading to confusion among practitioners and inconsistent patient care. 

RHD genotyping standardizes how clinicians treat patients with serologic weak D phenotypes.   Below, we explore how effective RHD genotyping is.

The Efficacy of RHD Genotyping for RhD Classification

RHD genotyping accurately identifies the specific gene variant associated with a patient’s serologic weak D phenotype. Individuals whom RHD genotyping identifies as having Weak D Types 1, 2 or 3, in the homozygous or hemizygous state, can be safely classified as RhD-positive, meaning that they will not form alloanti-D when exposed to RhD-positive RBCs through transfusion or pregnancy.

Individuals with RHD variants other than Weak D Types 1, 2 or 3 may be at risk for alloimmunization when exposed to RhD-positive RBCs. About 95% of Caucasian patients of European descent with serologic weak D phenotypes are Weak D Types 1, 2 or 3. 

Individuals of other ethnic backgrounds may have otherRHD variants, and may be at risk for alloimmunization. For this reason, the College of American Pathologists (CAP) and AABB Work Group recommend performing RHD genotyping on all patients with serologic weak D phenotypes or discordant RhD results—including pregnant women, newborns and potential transfusion recipients. RHD genotyping is the only definitive way to identify individuals with serologic weak D phenotypes who are in danger of alloimmunization to the D antigen following exposure to RhD-positive RBCs.

The Cost-Effectiveness of RHD Genotyping

A recent study by Kacker et al. estimated the financial implications across the entire healthcare system of performing RHD genotyping on obstetric patients with serologic weak D phenotypes.  Their highly detailed model compared the overall costs associated with RHD genotyping this select group of patients and treating them accordingly, versus the often practiced conservative strategy of managing these patients as RhD-negative and treating them prophylactically with Rh immune globulin (RhIG). Their model considered the increased cost of RHD genotyping, as well as the cost-savings associated with reducing unnecessary RhIG injections in patients with Weak D Types 1, 2 or 3.  

The results of this study indicated that implementation of RHD genotyping of pregnant patients with serologic weak D phenotypes would be essentially cost neutral over the entire healthcare system, and may lead to modest cost savings over time, given that RHD genotyping is a one-time test, whereas savings associated with reduced RhIG injections continue over subsequent pregnancies. A one-way sensitivity analysis also demonstrated that over a 10 year period, RHD genotyping of patients with serologic weak D phenotypes will result in overall cost savings if the cost per test is lower than $256.

Overall, RHD genotyping provides clinical value in the management of obstetrics patients without increasing the financial burden for healthcare facilities.

The Additional Benefits of RHD Genotyping

The benefits of decreasing unnecessary injections of RhIG are not only financial; reducing unwarranted administration of RhIG also avoids exposure to a human blood product pooled from multiple donors. In addition, RHD genotyping lessens the demand for transfusion of RhD-negative RBCs, always a limited resource, to patients who can safely receive RhD-positive RBCs. Lastly, RHD genotyping, as part of a standardized approach to the evaluation of patient RhD status, decreases confusion and inconsistencies in patient care. 

Overall, these benefits, together with modest cost savings over time, are expected to improve clinical management of obstetrics patients and transfusion recipients.

For more on RHD genotyping and its effectiveness, download your copy of “It’s time to phase in RHD genotyping for patients with a serologic weak D phenotype” by Sandler et al., 2015 here.