Recommendation for validation and quality assurance of non‐invasive prenatal testing for foetal blood groups and implications for IVD risk classification according to EU regulations

Abstract

Background and Objectives Non‐invasive assays for predicting foetal blood group status in pregnancy serve as valuable clinical tools in the management of pregnancies at risk of detrimental consequences due to blood group antigen incompatibility. To secure clinical applicability, assays for non‐invasive prenatal testing of foetal blood groups need to follow strict rules for validation and quality assurance. Here, we present a multi‐national position paper with specific recommendations for validation and quality assurance for such assays and discuss their risk classification according to EU regulations. Materials and Methods We reviewed the literature covering validation for in‐vitro diagnostic (IVD) assays in general and for non‐invasive foetal RHD genotyping in particular. Recommendations were based on the result of discussions between co‐authors. Results In relation to Annex VIII of the In‐Vitro‐Diagnostic Medical Device Regulation 2017/746 of the European Parliament and the Council, assays for non‐invasive prenatal testing of foetal blood groups are risk class D devices. In our opinion, screening for targeted anti‐D prophylaxis for non‐immunized RhD negative women should be placed under risk class C. To ensure high quality of non‐invasive foetal blood group assays within and beyond the European Union, we present specific recommendations for validation and quality assurance in terms of analytical detection limit, range and linearity, precision, robustness, pre‐analytics and use of controls in routine testing. With respect to immunized women, different requirements for validation and IVD risk classification are discussed. Conclusion These recommendations should be followed to ensure appropriate assay performance and applicability for clinical use of both commercial and in‐house assays.

Routine noninvasive prenatal screening for fetal Rh D in maternal plasma—A 2‐year experience from a single center in Belgium

“…Comparison of diagnostic accuracy however with other studies [9][10][11][12][13][14][15][16][17] is difficult, as the data in our study were achieved from a smaller sample size. 22 Nevertheless, we confirm fetal RHD testing as an excellent screening test for successful targeted RhIg prophylaxis.…”

“…The diagnostic accuracy of the analysis was high with a sensitivity and specificity reaching 100% (95% CI 95.3%–100.0% and 91.6%–100% respectively). Comparison of diagnostic accuracy however with other studies 9–17 is difficult, as the data in our study were achieved from a smaller sample size 22 . Nevertheless, we confirm fetal RHD testing as an excellent screening test for successful targeted RhIg prophylaxis.…”

Nichtinvasiver Pränataltest zur Bestimmung des fetalen Rhesusfaktors

“…Ein Transport bei Raumtemperatur ohne Temperaturüberwachung ist in der Regel möglich. Es ist ein schnellstmöglicher Transport zu wählen, sodass die Proben spätestens, wenn vom Testanbieter nicht anders angegeben, nach 5 Tagen im Labor sind 16 . Eine Blutentnahme vor Feiertagen sollte wegen der häufig verlängerten Transportzeit möglichst nicht durchgeführt werden.…”

Laboratory Monitoring of Mother, Fetus, and Newborn in Hemolytic Disease of Fetus and Newborn

“…As an antenatal screening to guide RhIg prophylaxis, non-invasive prenatal testing of fetal RHD has been introduced as a nationwide clinical service in several European countries [16][17][18][19][20][21][22][23][24][25]. Evaluations of national programs have demonstrated high test accuracy, with sensitivities of >99.9% around 25 weeks of gestation and >99% from GA 10 weeks [13].…”

“…Evaluations of national programs have demonstrated high test accuracy, with sensitivities of >99.9% around 25 weeks of gestation and >99% from GA 10 weeks [13]. Recent recommendations for validation and quality assurance of fetal RHD genotyping have been prepared [25].…”