Noninvasive fetal RHD testing is emerging as a standard of care: insights from a global survey

Written by Admin | May 19, 2026 2:45:27 PM

Alloimmunization against Rhesus D (RhD) is the leading cause of hemolytic disease of the fetus and newborn (HDFN) and occurs due to incompatibility between an RhD-negative mother and an RhD-positive fetus.¹

Noninvasive fetal RHD genotyping is used to screen nonimmunized RhD-negative pregnant women and guide targeted use of Rh immunoglobulin (RhIG) prophylaxis.² Since the discovery in 1998 that the RHD gene could be detected in maternal plasma, this approach has evolved into routine clinical practice in many countries.¹ In high-income regions, particularly in Europe, nationwide fetal RHD screening programs are now commonly part of standard care.³

Concerns are increasing around the need to restrict Rh prophylaxis due to the limited global availability of RhIG.^4,5 While monoclonal antibodies are being explored, none have yet shown clear effectiveness in preventing anti-D immunization, except Rhoclone, which still requires more extensive clinical validations.⁶ Moreover, RhIG use raises concerns related to infection risks from blood-derived products and ethical issues, such as donor immunization, payment, and restricted production to a few countries.³ In response, the American College of Obstetricians and Gynecologists (ACOG) recently issued a practice advisory recommending using noninvasive fetal RHD genotyping to help prioritize RhIG administration and preserve supplies during periods of RhIG shortage,^7,8 ensuring that anti-D prophylaxis is targeted only to those who will benefit, rather than administered to all RhD-negative women.⁹

To better understand the current state of noninvasive fetal blood group genotyping, the International Society of Blood Transfusion (ISBT) conducted a survey among participants in the noninvasive fetal RHD genotyping 4268DK program from the Danish Institute for External Quality Assurance for Laboratories in the health sector (DEKS), as well as members of the Red Cell Immunogenetics and Blood Group Terminology Working Party (RCIBGT).³

The survey included questions related to fetal RHD screening, and fetal RHD genotyping for RhD immunized women.³ In total, 52 laboratories across 22 countries participated, with the majority based in Europe, particularly in France, Germany, Denmark, and Sweden. This distribution reflects regions where noninvasive fetal antigen genotyping is already more established in clinical practice. The survey provides valuable insight into how noninvasive fetal antigen genotyping is currently implemented in clinical practice.

Implementation of noninvasive fetal RHD testing in clinical practice

Of the 52 participating laboratories, 38 (73%) perform fetal RHD screening, with the majority (27/38) operating within routine national programs. Real-time PCR is the dominant method, with 68% of laboratories using in-house assays targeting different combinations of RHD exons 4, 5, 7 and 10, and 32% using commercially available kits. Workflows are highly automated, particularly for cell-free fetal DNA (cffDNA) extraction from maternal plasma. In addition, most laboratories (87%) report fetal RHD results together with recommendations for Rh prophylaxis, reflecting strong integration into clinical decision-making. Overall, most laboratories report stable workflows, with limited plans for change; however, a subset is transitioning toward commercial solutions, reflecting a gradual shift toward standardized and regulated testing approaches.

Among laboratories performing fetal RHD screening, 79% use the same analytical approach for managing RhD immunized pregnancies. The remaining laboratories apply alternative methods, including droplet digital PCR (ddPCR) and other PCR-based techniques. While methodological approaches vary, the overall trend indicates reliance on established workflows, with additional quality measures such as fetal markers or repeat testing implemented to ensure accuracy.

The shift toward standardized solutions in fetal RHD screening and genotyping is evident in clinical laboratories. For example, the survey participants, Sahlgrenska University Hospital (Gothenburg, Sweden), as well as Department of Clinical Immunology and Transfusion Medicine at Lund University (Lund, Sweden), have implemented Devyser RHD, for noninvasive, single-exon fetal RHD genotyping, enabling efficient and reliable testing in routine practice.^3,10^,11

From insight to impact

Overall, the findings show that noninvasive fetal antigen genotyping is no longer an emerging technology, but an established part of clinical practice, particularly in Europe. The widespread adoption of routine screening programs and increasing testing early in pregnancy highlights its growing clinical value.

Noninvasive fetal genotyping supports both the prevention of alloimmunization and the management of already immunized pregnancies. With emerging therapies on the horizon, including monoclonal antibodies designed to inhibit IgG recycling and placental transfer,¹² early and accurate fetal antigen determination will become even more critical for guiding timely intervention, particularly in cases of early-onset severe anemia.

While the results primarily reflect high-income countries and European laboratories, where implementation is already advanced, they also highlight the need for broader global access and standardization. The relatively low prevalence of true RhD-negative women in Asia reduces the clinical demand for fetal RHD genotyping, which may partly explain the underrepresentation of Asian laboratories in this survey. Overall, the survey reflects both the maturity of the field and the opportunity for further expansion and harmonization of testing practices worldwide.

Devyser noninvasive fetal RHD genotyping solution

As noninvasive fetal RHD genotyping becomes increasingly recommended as a standard part of prenatal care across Europe, the UK, Australia, and New Zealand, reliable and scalable solutions are becoming more essential. Contact us to learn how the Devyser RHD kit can support accurate, efficient, and scalable noninvasive fetal RHD testing in your laboratory.

Disclaimer: Devyser products are distributed worldwide. Not all intended uses and applications mentioned here are available in every country. Please consult your local sales representative for details.

References

1. Clausen, F. B., & van der Schoot, C. E. (2025). Noninvasive fetal blood group antigen genotyping. Blood Transfusion, 23(2), 101–108. https://doi.org/10.2450/BloodTransfus.712

2. Clausen, F. B. (2024). Antenatal RHD screening to guide antenatal anti-D immunoprophylaxis in non-immunized D-negative pregnant women. Immunohematology, 40, 15–27.

3. Clausen, F. B., Hellberg, Å., Toly-Ndour, C., Nielsen, E. T., de Haas, M., & The Noninvasive Fetal Antigen Genotyping Survey Group. (2025). Noninvasive fetal antigen genotyping: Results from a survey on the status of clinical implementation. Vox Sanguinis, 120, 935–943.

4. Pegoraro, V., Urbinati, D., Visser, G. H. A., Di Renzo, G. C., Zipursky, A., Stotler, B. A., et al. (2020). Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children. PLoS ONE, 15, e0235807. https://doi.org/10.1371/journal.pone.0235807

5. Visser, G. H. A., Di Renzo, G. C., Spitalnik, S. L., & FIGO Committee Safe Motherhood and Newborn Health. (2019). The continuing burden of Rh disease 50 years after the introduction of anti-Rh(D) immunoglobulin prophylaxis: Call to action. American Journal of Obstetrics and Gynecology, 221, 227.e1–227.e4. https://doi.org/10.1016/j.ajog.2019.05.036

6. Verweij, E., Tura, A. K., Gure, T., Pyuza, J., Mchome, B., Kawaza, K., et al. (2024). Monoclonal RhD prophylaxis: High time to evaluate efficacy. The Lancet, 403(10430), 806–807. https://doi.org/10.1016/S0140-6736(24)00431-4

7. American College of Obstetricians and Gynecologists. (2024a). Rho(D) immune globulin shortages: Practice advisory. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2024/03/rhod-immune-globulin-shortages

8. American College of Obstetricians and Gynecologists (ACOG). (2024b). ACOG clinical practice update: Paternal and fetal genotyping in the management of alloimmunization in pregnancy. Obstetrics & Gynecology, 144, e47–e49.

9. Wikman, A. (2024). Fetal RHD screening in clinical routine (Expert review). Devyser.

10. Isakson, P., & Pardi, C. (2023). Evaluation of an automated platform for non-invasive single-exon fetal RHD genotyping early in pregnancy. Blood Transfusion, 21(6), 472–478. https://doi.org/10.2450/2023.0267-22

11. Pardi, C., Hellberg, Å., & Isakson, P. (2024). Single-exon fetal RHD genotyping: A 31-month follow-up in the obstetric population of Western Sweden. Blood Transfusion, 22(5), 387–394. https://doi.org/10.2450/BloodTransfus.741

12. Komatsu, Y., Verweij, E. J. T. J., Tiblad, E., Lopriore, E., Oepkes, D., Agarwal, P., et al. (2025). Design of a phase 3, global, multicenter, randomized, placebo-controlled, double-blind study of nipocalimab in pregnancies at risk for severe hemolytic disease of the fetus and newborn. American Journal of Perinatology, 42, 842–853. https://doi.org/10.1055/a-2404-8089

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