Original Title: Cribado prenatal para la detección del síndrome de Down mediante el análisis de ADN fetal en sangre materna

Authors' objectives: 1. To describe the diagnostic accuracy (sensitivity, specificity and positive and negative predictive values) and the analytical validity (failure rate) of prenatal tests based on the analysis of cell-free fetal DNA in the maternal blood for the detection of T21. 2. To carry out an economic analysis comparing the application of the new DS detection technology, using cell-free fetal DNA in maternal blood in prenatal diagnosis, with the prenatal diagnosis and screening procedures currently applied in the Basque Country.

Authors' results and conclusions: The grouped sensitivity for DS derived from 40 studies (n=203,346) was 99.3% (95% CI: 98.9% to 99.6%) and the grouped specificity was 99.9% (95% CI: 99.9% to 100%). The estimations of grouped sensitivity were 1.4% greater in the high-risk population compared with the general obstetric population for DS. The precision of the NIPT estimated in the high-risk obstetric population was 324 DS cases detected per 10,000 pregnancies, with nine non-detected cases and 31 false positives. Consequently, 91% of the high-risk pregnancies with positive results in NIPTs will have DS. In the general obstetric population, the positive predictive value was lower. Thus, in 100,000 pregnancies in the general obstetric population, 417 cases of DS will be detected, with 18 non-detected cases and 94 false positive cases. Therefore, 82% of the pregnancies in the general population with positive NIPT results will have DS. The sensitivity was higher in single pregnancies compared with twin pregnancies (97.7% vs 89.4%), but, as expected, large variations in specificity were not observed (99.8% vs 99.6%). The rate of analytical failure (failure of the NIPT) varied between 0% and 12.7%. In another meta-analysis, which included 21 studies on the diagnostic performance of NIPT to detect DS in single pregnancies (n=222,659), the grouped weighted detection rate and rate of false positives was 99.2% (95% CI: 98.5% to 99.6%) and 0.09% (95% CI: 0.05% to 0.14%), respectively. The results of the model indicate that, for the baseline case, where the cut-off point is ≥1:270, the use of NIPT as contingent test, compared with the current prenatal screening program, detects two cases less of DS (269 vs 271) and causes a lower number of miscarriages related to IT (4 vs 23) at a slightly lower cost (€ 8,111,351 vs € 8,901,872), meaning that it cannot be considered a cost-effective option. When the risk cut-off point is established at 1:500 or 1:1000 for the contingent NIPT, the number of DS cases detected increases, as does the cost. The number of miscarriages related to IT is similar. The cost-effectiveness analysis indicated that when the latter strategy is compared with the current prenatal screening tests, it could be cost-effective (€ 61,763 or € 256,123 per extra DS case detected, respectively). Using the NIPT as the primary test, compared with current prenatal screening, detects a larger number of DS cases (296 vs 271) and causes a lower number of miscarriages related to IT (5 vs 23), at a substantially higher cost (€ 41,395,645 vs € 8,901,872). The cost-effectiveness analysis indicated that, when NIPT used as primary screening tests are compared with the current prenatal screening, the first alternative is more expensive and more effective. The incremental cost was € 1,299,763 per extra DS case detected. Finally, the comparison between NIPT as the primary screening test compared with NIPT as contingent test showed that the first alternative is more expensive and more effective, with an incremental cost of € 1,232,763 per extra DS case detected. The univariant sensitivity analysis showed that a decrease in the price of the NIPT from € 550 (baseline case) to € 150 or to € 76, would cause a decrease in the cost of the prenatal screening program both when NIPT are used as contingent tests or as the primary screening test. Thus, for the first case, at a price of € 150 or € 76, the cost of the screening program decreases by 16.16% or by 19.15%, respectively, whereas for the second case, the decrease is 70.48% or 83.51%, respectively. When the price of the NIPT is € 76 and the new technique is used as the primary screening test, the alternative is dominant (i.e., more effective and cost saving), compared with current prenatal screening. It is also cost-effective compared with the NIPT as contingent test (€ 9,869 per extra DS case detected). The univariant sensitivity analysis, when the screening coverage of the screening program increases to 89.97% using the NIPT as the primary test compared with the current prenatal screening, showed similar results to those derived from the baseline case, with a larger number of DS cases detected (341 vs 271) and less miscarriages related to the IT (5 vs 23), but at a much higher cost (€ 47,524,533 vs € 8,901,872). The joint modification of the price of the NIPT and of the coverage rate (bivariant analysis), does not change the results set out above. CONCLUSIONS The high quality evidence indicates that, despite the high accuracy, the NIPT cannot be considered diagnostic for DS and cases with positive results must be confirmed using the genetic analysis following invasive tests, such as amniocentesis or corial biopsy, in order to confirm the presence of T21. However, in single pregnancies, the screening performance of NIPT for DS is higher than other screening strategies that combine the mother’s age with serological and sonographic markers. The main strength of the economic analysis is that the model has been constructed on real data obtained from the register of the Prenatal Down Syndrome and other Chromosome Abnormalities Screening Program (PCP) of the Basque Country, launched in 2009. The use of NIPT as a contingent test in a DS screening program, for a risk cut-off point of ≥1:270 and a price per NIPT of € 550 —even though does not detect more cases of T21, which turns it into a non-cost-effective option—, seems to offer some benefits compared with the current prenatal screening, given that decreases the number of cases of miscarriages related to IT. A decrease up to a risk cut-off point of ≥1:500, would cause a larger number of DS cases detected, at a 4% higher cost and, therefore, such scenario could become a cost-effective alternative. The use of NIPT as the primary test in a DS screening program, at a price per NIPT of € 550, seems to offer benefits compared with the current screening with a cut-off point of ≥1:270, as increases the number of DS cases detected and decreases the cases of miscarriages related to IT, although at a much higher cost. The use of NIPT as the primary test would be a cost-effective alternative as compared to the current screening program, if the price per test decreases until it becomes similar to the price of the serological screening tests used at present. The present report exclusively addresses the prenatal screening of DS, so no other congenital abnormalities or chromosome disorders are assessed, although such disorders may also be detected prenatally using NIPT.

Authors' methods: Objective no. 1 was addressed through an overview, by conducting a narrative review of the scientific literature. Evidence about the precision of NIPT was obtained from two recently published high methodological quality meta-analyses. To achieve objective No. 2, an economic analysis was conducted from the perspective of the financing body of the National Health System in order to compare different prenatal screening strategies for the detection of DS in a general population of pregnant women. An analytical decision model (decision tree) was developed, based on the Belgian model developed by Hulstaert and cols., to assess the costs and consequences, comparing the current prenatal screening, NIPT as contingency tests in high-risk cases and NIPT as first-line screening tests (i.e., as a substitute to current screening tests). The main outcome measure was the number of DS cases detected. Other outcome measures were: the total number of women on whom current screening tests would be carried out, the total number of women on whom NIPT would be carried out, the number of NIPT with positive results, the number of IT carried out and the number of miscarriages related to IT aimed at confirming the diagnosis. The total direct health costs related to the screening were calculated for each procedure. Twin pregnancies were excluded from the model. An economic analysis was conducted to determine which of the screening strategies analysed was more cost-effective by means of the incremental cost-effectiveness ratio calculation. Likewise, univariant and bivariant sensitivity analyses were performed to explore the effect that a variation in the cost of NIPT, the cut-off risk point for DS when NIPT were used as contingent tests, and prenatal screen coverage when NIPT were used as a primary test, could have on the economic analysis.

Project Status: Completed

Year Published: 2016

URL for published report: https://www.ogasun.ejgv.euskadi.eus/r51-catpub/es/k75aWebPublicacionesWar/k75aObtenerPublicacionDigitalServlet?R01HNoPortal=true&N_LIBR=051918&N_EDIC=0001&C_IDIOM=es&FORMATO=.pdf

English language abstract: An English language summary is available

Publication Type: Rapid Review

Country: Spain

Organisation Name: Basque Office for Health Technology Assessment

Contact Address: C/ Donostia – San Sebastián, 1 (Edificio Lakua II, 4ª planta) 01010 Vitoria - Gasteiz

Contact Name: Lorea Galnares-Cordero

Contact Email: lgalnares@bioef.eus

Copyright: <p>Osteba (Basque Office for Health Technology Assessment) Health Department of the Basque Government</p>