Noninvasive Fetal RhD Blood Group Genotyping: A Health Technology Assessment.

Abstract

Background: RhD blood group incompatibility during pregnancy can cause serious health problems for the fetus. Noninvasive fetal RhD blood group genotyping is a test for fetal RhD status that may help prevent unnecessary preventive treatment (Rh immunoglobulin [RhIG] injections) and intensive pregnancy monitoring. We conducted a health technology assessment of noninvasive fetal RhD blood group genotyping for RhD-negative (RhD-) pregnancies. Our assessment evaluated the test's diagnostic accuracy, clinical utility, and cost-effectiveness, the budget impact of publicly funding this test, and patients' and providers' preferences and values.

Methods: We performed a systematic literature search of the clinical and economic evidence to conduct an overview of reviews for test accuracy, a systematic review for clinical utility, and a review of the test's cost-effectiveness compared with usual care. We assessed the risk of bias of each included systematic review and study using the ROBIS and RoBANs tools, respectively. We assessed the quality of the body of clinical evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We developed probabilistic Markov microsimulation models to determine the cost-effectiveness and cost-utility of noninvasive fetal RhD genotyping compared with usual care from the Ontario Ministry of Health perspective. We also estimated the 5-year budget impact of publicly funding this test in Ontario. To examine patient and provider preferences related to noninvasive fetal RhD genotyping, we conducted a literature survey of quantitative studies on preference; the Canadian Agency for Drugs and Technologies in Health (CADTH) performed a review of qualitative literature about patient preferences; and we conducted interviews and an online survey with Ontario patients.

Results: We included six systematic reviews in the overview of reviews on diagnostic test accuracy and 11 studies in the clinical utility review. Across systematic reviews, test accuracy was high for noninvasive fetal RhD genotyping. The evidence suggests that implementation of noninvasive fetal RhD genotyping may lead to avoidance of unnecessary RhIG prophylaxis (GRADE: Low), good compliance with targeted RhIG prophylaxis (GRADE: Very low), and high uptake of genotyping (GRADE: Low). Alloimmunization may not increase when using noninvasive fetal RhD genotyping to target prenatal RhIG prophylaxis (GRADE: Very low), and may allow unnecessary monitoring and invasive procedures to be avoided in alloimmunized pregnancies (GRADE: Very low).We included eight published economic studies that reported inconsistent results regarding the cost-effectiveness of noninvasive fetal RhD genotyping. In nonalloimmunized RhD- pregnancies, compared with usual care, the intervention identified more maternal alloimmunization cases (probability: 0.0022 vs. 0.0020) and was associated with a reduced number of RhIG injections per pregnancy (1.79 vs 1.43). It was more expensive ($154, 95% credible interval [CrI] $139 to $169) but had little impact on the QALYs of newborns followed over a 10-year time horizon (0.0007, 95% CrI -0.01 to 0.01). The cost of noninvasive fetal RhD genotyping and inclusion of paternal RhD typing were drivers of the cost-effectiveness results in this population. In alloimmunized RhD- pregnancies, noninvasive fetal RhD genotyping was associated with lower resource use during the pregnancy. Compared with usual care, it was less costly (-$6,280, 95% CrI -$6,325 to -$6,229) and more effective (0.19 QALYs, 95% CrI 0.17 to 0.20).The annual budget impact of publicly funding noninvasive fetal RhD genotyping in nonalloimmunized RhD- pregnancies in Ontario ranges from $2.6 million in year 1 (uptake of 80%) to $3.4 million in year 5 (uptake of 100%), with a 5-year total of about $14.8 million. In alloimmunized pregnancies, we estimate cost savings, from about $9 million in year 1 to about $12 million in year 5, with 5-year total savings of about $51.5 million.We included two studies in the survey of quantitative preferences literature. In the quantitative literature, RhD- pregnant people support routine offering of noninvasive fetal RhD genotyping as part of pregnancy care, with a preference to be adequately informed about the test process, attributes, timing, and risks in advance of the test, ideally in a dialogue with their health care provider. More than half of obstetric health care providers were supportive of offering the test. The qualitative review by CADTH and our own engagement with Ontario patients yielded similar results. Participants consistently expressed a desire for more information about the test and assurance about its safety. They also consistently mentioned the prevention of unnecessary monitoring and treatment as potential benefits.

Conclusions: Noninvasive fetal RhD blood group genotyping is an accurate test to determine RhD incompatibility and guide management of RhD- pregnancies. Compared with usual care, noninvasive fetal RhD genotyping is less costly and more effective for the management of alloimmunized pregnancies. For nonalloimmunized pregnancies, noninvasive fetal RhD genotyping would generally not be considered cost-effective, compared with usual care, unless the cost of testing is much lower than what is proposed now. Publicly funding noninvasive fetal RhD genotyping for guiding the management of RhD- pregnancies in Ontario over next 5 years is associated with a total budget impact of about $15 million in nonalloimmunized pregnancies and total cost savings of about $51 million in alloimmunized pregnancies. Patients and providers indicated support for the routine use of noninvasive fetal RhD genotyping in RhD- pregnancies.