Which Patients Should be Tested With RHD Genotyping?

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Determination of RhD type is critical to preventing sensitization and antibody production (alloimmunization) in blood transfusion recipients and pregnant women.  However, the standard serologic method of determining RhD status can lead to inconsistent clinical management for patients with weak or variable RhD types that are caused by genetic variation in the RHD gene.

Below, we explore how RhD typing may produce equivocal or unclear results and discuss which patients should be tested with RHD genotyping to more accurately determine RhD status for treatment.

Why Has the Management of Patients with Weak or Variable RhD Types Been Inconsistent?

As recently as five years ago, it was standard practice to determine the RhD status of a patient using only serologic testing, that is testing the patient’s red blood cells with anti-D (antibody) and looking for agglutination (RhD positive) or no agglutination (RhD negative). But some patients have what is referred to as a serologic weak D type, characterized by red blood cells that are initially non-reactive or only react weakly with anti-D. Historically, patients with a weak D type, especially pregnant women, were sometimes managed as RhD-negative and in some cases, clinicians treated these patients as RhD-positive.

Observational studies have shown that patients with Weak D Types 1, 2 or 3 as determined by RHD genotyping are not at risk for sensitization (antibody production) when exposed to conventional RhD-positive red blood cells. These individuals can, therefore, be treated as RhD-positive in pregnancy and for transfusion and do not need Rh immune globulin (RhIG) in pregnancy.

The unequivocal identification of patients with Weak D Types 1, 2 or 3 by RHD genotyping is therefore important in reducing both the unnecessary use of Rh immune globulin (RhIG) and transfusion of RhD-negative red blood cells, a limited resource, when RhD-positive red cells could be safely transfused. RHD genotyping of patients with serologic weak D types is now a common and reliable method, utilizing molecular biology techniques that can specifically identify the many different RHD genetic variants for proper patient management in a clinical setting.

Who Should be Tested with RHD Genotyping?

It has been estimated that out of ~3.95 million live births in the U.S. annually, RHD genotyping could identify 13,360 individuals with Weak D Types 1, 2, and 3, avoiding approximately 24,700 unnecessary injections of RhIG nationwide. Likewise, of ~5 million individuals transfused annually in the U.S., RHD genotyping could identify ~17,520 individuals with Weak D Types 1, 2 or 3 who could safely receive 47,700 units of RhD-positive blood rather than receiving RhD-negative blood, which is always in short supply.

However, currently it would be impractical to perform RHD genotyping on all blood recipients and all pregnant women to identify the few individuals with Weak D Types 1, 2 or 3. To maximize the benefit of RHD genotyping, the College of American Pathologists (CAP) and AABB convened a Work Group that developed recommendations for implementing RHD genotyping for a selective group of patients. 

The Work Group recommends that currently RHD genotyping be performed on both pregnant women and females of child bearing potential who need transfusion, who present with a weaker than expected RhD typing test or who have variable or discordant RhD typing results or whenever the RhD type is in question. Those individuals with RHD genotyping indicating Weak D Types 1, 2 or 3 can be managed as RhD-positive. On the other hand, patients for whom RHD genotyping identifies RHD variants called “partial D” should be treated as RhD-negative, meaning they are candidates for RhIG prophylaxis and should receive RhD-negative blood if transfused.

Why Should Clinicians Phase In RHD Genotyping?

The CAP/AABB Work Group recognizes that most healthcare facilities can’t justify on-site RHD genotyping given the low number of patients with uncertain RhD typing and the expertise necessary for performing RHD genotyping of this select group of patients.  Use of reference laboratories promotes standardization of testing and economy of large-scale genotyping.  Financial analysis of implementing the Work Group recommendations has demonstrated that the strategy of RHD genotyping female patients with a weak D type or discordant RhD results is cost neutral over the entire healthcare system, given the associated cost savings of avoiding unnecessary RhIG injections and testing of the mother and fetus. Importantly, there is a benefit in preserving RhD-negative RBC units for transfusion to patients and neonates who truly require them.

This selective phasing in of RHD genotyping will result in consistent clinical management for patients with serologic weak D types. Furthermore, RHD genotyping promotes the appropriate use of critical resources such as RhIG injections and RhD-negative blood for transfusion.  In the future, due to genetic variation in RhD status across populations, RhD typing will be routinely performed by RHD genotyping particularly for pregnant women.

For more on the Work Group’s recommendations, 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. You can also find additional information in the 2015 Haspel and Westhoff study, "How do I manage Rh typing in obstetric patients?".