Original Title: Avis: génotypage du RhD fœtal par test prénatal non invasif (plasma maternel)

Authors' objectives: Hemolytic disease of the fetus and newborn (HDFN) is caused by maternal alloimmunization, which occurs when antibodies from the mother are directed against antigens (rhesus D; RhD) present on the surface of fetal red blood cells and cause their destruction. The consequences of HDFN range from jaundice and mild fetal anemia to fetal or neonatal death. Currently, to prevent the maternal alloimmunization that occurs as a result of maternal-fetal RhD incompatibility, routine prenatal prophylaxis is offered to RhD-negative women around the 28th week of pregnancy, during potentially sensitizing events during pregnancy, and within the 72 hours following the birth of an RhD-positive newborn. It is known that the administration of these prophylaxis, which is derived from human plasma, is associated with a risk, albeit very low, of pathogen transmission and allergic reactions. Pregnant women known to be alloimmunized are rigorously managed by way of high-risk pregnancy (HRP) monitoring. However, according to the scientific literature, nearly 40% of RhD-negative pregnant women carry an RhD-negative fetus and are therefore not at risk for alloimmunization. Since the vast majority of these women are non-alloimmunized, prophylaxis is administered unnecessarily, whereas in previously alloimmunized women, HRP monitoring should not be done because of the unborn child’s RhD-negative status. By permitting the determination of the fetus’s RhD status early in pregnancy, maternal plasma-based fetal RhD genotyping would make it possible to avoid these interventions in these women. Héma-Québec would like to offer all pregnant women in Québec who are known to be RhD-negative a molecular test for determining the unborn child’s RhD status from fetal DNA circulating in the mother's blood. Fetal RhD genotyping consists in extracting fetal DNA from maternal plasma and detecting the RHD gene sequences on several exons using a real-time quantitative nucleic acid amplification test (NAAT). A commercial kit, which has yet to be decided on, or an "in-house" test would be used. Currently, no commercial kit for noninvasive prenatal testing for fetal RhD genotype has been approved by Health Canada for clinical use.

Authors' results and conclusions: RESULTS: (CLINICAL VALIDITY) A search of the scientific literature on the clinical validity of fetal RhD genotyping yielded 1 health technology assessment (HTA) report, 2 systematic reviews with meta-analysis, and 13 primary studies published after the HTA report. The currently available scientific data support high clinical performance in the "Caucasian" population. Uncertainty remains as to the transposability of this performance to the Québec context. The rate of false-negative results reported in the studies is low, and the diagnostic accuracy is higher after the 11th week of pregnancy. (CLINICAL UTILITY) Compliance with fetal RhD screening is very high in the countries where it has been implemented. Based on the available data, anti-D Ig administration as prenatal prophylaxis could be avoided in 25% to 39% of non-alloimmunized RhD-negative pregnant women. No evidence was found regarding the proportion of alloimmunized RhD-negative pregnant women for whom testing could obviate the need for HRP monitoring. Little or no data is available on the impact of false-negative results on the risk of alloimmunization. An increase in adverse events associated with anti-D Ig has been observed in recent years. However, the number of events is very low, considering the amount of anti-D Ig administered in Québec annually. (ISSUES AND STAKEHOLDER PERSPECTIVE) The published clinical data indicate that the test is effective, but the uncertainties in the choice of method are highly likely to influence the test’s clinical performance and its cost-effectiveness. In addition, several organizational issues were raised during the consultations with women and with experts in perinatal medicine, genetics, hematology, transfusion safety and molecular biology, such as the implementation of genotyping in clinical practice, sample transport and storage, the transmission of results, and training for the various stakeholders. The experts point out that, currently, midwives who provide care to RhD-negative pregnant women would not be able to order this test. In addition, ethical concerns were raised regarding the administration of a blood product to women who do not require it, given the existence of a noninvasive genotyping test, despite the fact that the risks inherent in genotyping are poorly documented. The stakeholders consulted consider it essential that women be able to make an informed choice between the two treatment options, this in accordance with their values and beliefs. (ECONOMICS) The results of the literature search regarding the cost-effectiveness of targeted prophylaxis guided by fetal RhD genotyping are not transposable to clinical practice in Québec. INESSS therefore developed its own models. Since the requester has not yet decided on a kit, the modeling is based on clinical performance data from the scientific literature. The results of INESSS’s modeling, which are accompanied by uncertainties, indicate that fetal RhD genotyping would be a potentially cost-effective approach for RhD-negative pregnant women who are alloimmunized, while it would unlikely be cost-effective for those who are not alloimmunized. It should be noted that these results are transposable only if the kit that is chosen achieves the clinical performance reported in the literature. The possible inclusion of this test in the Répertoire québécois et système de mesure des procédures de biologie médicale for this alloimmunized patient population could lead to annual cost reductions of approximately $45,000 for the next 3 years, while additional costs of approximately $500,000 for the same period are expected for the non-alloimmunized population. (POSITIONS AND ORIENTATIONS OF ORGANIZATIONS OF INTEREST) The Society of Obstetricians and Gynaecologists of Canada (SOGC), among other organizations that have spoken on this matter, recommends implementing such testing in order to optimize the management of RhD-negative pregnant women.

Authors' recommendations: The members of the Comité scientifique permanent des analyses de biologie médicale (CSABM) and the Comité d’excellence clinique (CEC) en services de santé recognized the clinical value of noninvasive fetal RhD genotyping using maternal plasma for RhD-negative women in Québec. However, they noticed that it would be too early to include it in the Répertoire québécois et système de mesure des procédures de biologie médicale because of various uncertainties regarding the method and its implementation. In light of the available data, INESSS recommends that fetal RhD genotyping using maternal plasma not be included in the Répertoire. However, this test could be offered to the target population in the event: In light of the available data, INESSS recommends that fetal RhD genotyping using maternal plasma not be included in the Répertoire. However, this test could be offered to the target population in the event: • that the method chosen (commercial kit or "in-house” test) be specified and that its performance and limitations are determined prospectively through a validation study carried out in real-world care settings. During this validation period, the risk of false-negative results should be mitigated by maintaining confirmatory RhD testing of cord blood in the postpartum period, and access to anti-D Ig should be maintained to ensure the safety of women and their fetus; • that, based on this new data, the offer of service is recognized as being effective and safe and that the costs it entails are acceptable relative to the clinical benefits obtained.

Authors' methods: A rapid review of the scientific literature was conducted to document the various aspects related to the performance, clinical utility, ethics and cost-effectiveness of fetal RhD genotyping tests. The current management of RhD-negative women and the various ethical and organizational issues pertaining to the possible implementation of prenatal genotyping were considered and summarized following consultations with various stakeholders. In addition, economic analyses were performed using the available data.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/genotypage-du-rhd-foetal-par-test-prenatal-non-invasif-plasma-maternel.html

Year Published: 2021

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/genotypage-du-rhd-foetal-par-test-prenatal-non-invasif-plasma-maternel.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec