Original Title: Resultados comparados de las distintas estrategias de cribado para el t21, T18 y T13: adaptación del informe EUnetHTA

Authors' objectives: The main objective is to assess the comparative safety and effectiveness of the main prenatal screening strategies including cfDNA for the detection of trisomies 21 (T21), 18 (T18) y 13 (T13), establishing the diagnostic accuracy (intermediate variables), as well as the implications in terms of relevant outcomes for the pregnant women and/or fetus. The report also aims to analyse the costs and the main organizational, ethical and social issues related to the implantation of the different screening strategies at the national level.

Authors' results and conclusions: Results: the meta-analysis of the diagnostic accuracy of NIPT as a primary testing method for T21 in singleton pregnancies (total replacement of FCT), calculated based on 136 544 pregnant women (885 aneuploid and 135659 euploid cases), yielded a pooled estimate of sensitivity (S) of 99.3 [95 %CI 97.8 to 99.8], using the bivariate effect model. The specificity (Sp) was 99.9 [95 %CI 99.8 to 99.9] excluding miscarriages, fetal losses and uncertaing/ indeterminate/no call results. Based on the accuracy data of the Cochrane review, the estimated pooled sensitivity of FCT for the risk level of 1:300 is estimated to be 87.26 [95 %-CI 85.18 to 89.09] and the estimated pooled specificity is 95.50 % [95 %CI 94.86 to 96.05]. Therefore, if an indirect comparison is carried out, assuming a prevalence of T21 of 24:10 000 pregnant women (EUROCAT data), the positive predictive value of NIPT as a primary test would be 82.6 % in comparison to 4.4 % for the FCT, with cero false negatives versus 0.03 %. In this hypothetical scenario, the detection rate would increase slightly (29 extra cases detected in 100 000 screened women) and the number of invasive test would be reduced. If we assume that around 90 % of all of the women that would test positive would undergoe invasive testing, a substantial reduction in invasive testing would be expected (4233 out of 100 000 screened women would undergoe invasive testing with the FCT strategy versus 259 with NIPT as a primary test). The pooled sensitivity, estimated based on twenty four studies (1408 aneuploidy cases and 99818 euploid cases) which provided data on the accuracy of NIPT as a second tier test was 99.21 %, 95 %CI 98.59 to 99.56 and Sp reached 99.95 %, 95 %CI 99.93 to 99.96. Based on this data and on the accuracy data of the Cochrane review, assuming that all women testing positive with FCT would undergo NIPT testing, the estimated sensitivity of the add-on strategy (FCT + NIPT) for a hypothetical cohort of 10 000 would be 86.8 % [95 % CI 82.2 %-90.4 %]. Estimated specificity would be 100 % [95 % CI 99.9 %-100 %]. The positive predictive value would be 99.1 % [95 % CI 96.7 %-99.7 %] and the negative predictive value 100 % [95 % CI 99.9 %-100 %]. In this hypothetical scenario de contingent strategy would lead to two additional false negatives in 100 000 screened women. Assuming that 90 % of the women testing positive would undergo confirmation, 189 would be prone to invasive procedures with contingent screening in comparison to 4238 with FCT. Both NIPT strategies (NIPT only or FCT+NIPT) show advantages and inconveniences when they are compared against each other. The use of NIPT as a sole screening test would lead to an important reduction in the number of non detected cases in comparison to contingent screening (2 versus 1000 screened women) but would in turn occassionate a greater number of invasive tests. As a contingent test, the detection rate will not increase with regards to FCT, on the contrary, there is a possibility of missing some cases, although less invasive testing is expected. The total estimated costs for a population of 100 000 pregnant women, assuming a prevalence of T21 of 24:10 000 would be 9 739 077 € for the FCT strategy, 8682160 for the contingent strategy (FCT+NIPT) and 28 764 629 € for the NIPT only strategy. For T18, the pooled sensitivity of NIPT as a primary screening test calculated applying the bivariate random-effect model, was estimated to be 96.86 % [95 %CI 88.35 % to 99.21 %] and pooled Specificity was 99.97 [95 %CI 99.93 to 99.98]. However, the model was unreliable due to the lack of variability in the specificity and the great number of aneuploidy cases (234 versus 135405). Due to this fact and the low quality of the evidence, it was not considered appropriate to do any modelling. Discussion: the quality of evidence of the studies on T21 that assess the use of NIPT as a primary or secondary testing method was moderate for sensitivity and low for specificity (GRADE approach). The main limitation of the studies was the high risk of bias. The follow up was incomplete in all of the studies and the two studies that contribute mostly to the results of NIPT as a first tier test, given their sample size, showed losses of 16.4 % and 23 %. In addition, the verification of the negative results of the cfDNA test was based on registries, medical databases or interviews, raising important uncertainties regarding the reliability of the specificity results. The applicability of the estimations of the positive predictive value and negative predictive was also doubtful given that the prevalence of T21 in the included studies was not representative of that found in the general population. The exclusion of miscarriages, fetal lossess and uncertain/no call results could have led to an overestimation of the specificity for both the general and high-risk population. In general, the studies on T18 and T13 have very low statistical power due to the small simple size and this can explain the lack of false positives or false negatives for these aneuploidies. Conclusions: 1) existing evidence supports that the sensitivity for T21 is significantly higher for NIPT than for FCT, when used as a first tier screening test, and that the replacement of FCT by NIPT would lead to a considerable reduction in unnecessary invasive testing. The generalisability of the positive predictive value and negative predictive value is limited by the fact that the prevalence of T21 was not representative of that found in general pregnant population; 2) available data also suggests that the use of NIPT as an add-on to combined testing for high risk T21 population screening could also lead to substantial reductions in unnecessary invasive. However, this results needs to be confirmed with real world data. The performance of the test (test failures, uncertain results) and the uptake of NIPT screening are amongst the factors that could contribute to change this ratio in real practice. 3) the low quality of the evidence for T18 and T13 does not allow for drawing conclusions on these trisomies for any of the screening pathways. 4) uncertainty remains regarding the diagnostic accuracy of NIPT testing in twin pregnancies. 5) Appropriately designed prospective comparative studies are required in order to be able to assess the performance of the different test strategies, taking into account detection of all abnormalities, abortions, miscarriages and other patient related outcomes. To date, important uncertainties remain regarding the best screening pathway.

Authors' methods: Methods: adaptation of the European Network of Health Technology Assessment (EUnetHTA) report “Screening of fetal trisomies 21, 18 and 13 by non invasive prenatal screening” carried out by the health technology assessment unit of the Galician Agency for Health Knowledge Management (Avalia-t; ACIS) in 2018. In line with the recommendations of the “guideline for elaboration and adaptation of rapid health technology assessment” developed within the framework of the RedETS, the report incorporates the main results of the assessment and complements existing information with national data wherenever contextualization is possible.

Project Status: Completed

Year Published: 2020

URL for published report: http://hdl.handle.net/20.500.11940/14401

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Spain

Organisation Name: Scientific Advice Unit, avalia-t; The Galician Health Knowledge Agency (ACIS)

Contact Address: Conselleria de Sanidade, Xunta de Galicia, San Lazaro s/n 15781 Santiago de Compostela, Spain. Tel: 34 981 541831; Fax: 34 981 542854;

Contact Name: avalia-t@sergas.es

Contact Email: avalia-t@sergas.es

Copyright: <p>Galician Agency for Health Technology Assessment (AVALIA-T)</p>