Routinization of prenatal screening with the non-invasive prenatal test: pregnant women’s perspectives

Due to the favorable test characteristics of the non-invasive prenatal test (NIPT) in the screening of fetal aneuploidy, there has been a strong and growing demand for implementation. In the Netherlands, NIPT is offered within a governmentally supported screening program as a first-tier screening test for all pregnant women (TRIDENT-2 study). However, concerns have been raised that the test’s favorable characteristics might lead to uncritical use, also referred to as routinization. This study addresses women’s perspectives on prenatal screening with NIPT by evaluating three aspects related to routinization: informed choice, freedom to choose and (personal and societal) perspectives on Down syndrome. Nationwide, a questionnaire was completed by 751 pregnant women after receiving counseling for prenatal screening. Of the respondents, the majority (75.5%) made an informed choice for prenatal screening as measured by the multidimensional measure of informed choice (MMIC). Education level and religious affiliation were significant predictors of informed choice. The main reason to accept screening was “seeking reassurance” (25.5%), and the main reason to decline was “every child is welcome” (30.6%). The majority of respondents (87.7%) did not perceive societal pressure to test. Differences between test-acceptors and test-decliners in personal and societal perspectives on Down syndrome were found. Our study revealed high rates of informed decision-making and perceived freedom to choose regarding fetal aneuploidy screening, suggesting that there is little reason for concern about routinization of NIPT based on the perspectives of Dutch pregnant women. Our findings highlight the importance of responsible implementation of NIPT within a national screening program.

A ritka kromoszóma-rendellenességek és a fetoplacentaris mozaikosság jelentősége a praenatalis diagnosztikában a nem invazív szűrővizsgálatok tükrében

Összefoglaló. Bevezetés és célkitűzés: A gyakori autoszomális trisomiák és a nemi kromoszómaeltérések a mikroszkóppal észlelhető kromoszóma-rendellenességek kb. 80–85%-át képviselik. A ritka kromoszóma-rendellenességek klinikai következménye jelentős, kimutatásukat a jelenlegi szűrővizsgálatok ugyan nem célozzák, de a teljes kromoszómaszerelvényt vizsgáló, nem invazív praenatalis tesztelés új lehetőséget nyitott a korai felismerésükre. Módszer: Retrospektív analízis (2014–2019) a mikroszkóppal kimutatható kromoszóma-rendellenességek eloszlására, a fetoplacentaris mozaikosság előfordulására, klinikai összefüggéseire a praenatalis vizsgálatok tükrében egy hazai tercier centrumban. Eredmények: 2504 invazív beavatkozást végeztünk és 200 kromoszómaeltérést mutattunk ki (8%), melyek közül újonnan kialakult, ritka rendellenesség 27 volt (13,5%). Ritka autoszomális trisomia 14, poliploidia 6, de novo szerkezeti kromoszómaeltérés 5, marker kromoszóma 2 esetben igazolódott. A fetoplacentaris mozaikosság aránya a gyakori/ritka kromoszómaeltérésekben 12,4%/77,8% volt (p = 0,001), 17/40 esetben lepényre korlátozódott. A gyakori trisomiákkal kóros tarkóredő-vastagság 58%-ban, major ultrahangeltérés 35%-ban társult, melyek jelentősen különböztek a ritka kromoszómaeltérésekben (11%, p = 0,006; 67%, p = 0,047). A ritka kromoszómaeltérések jellemző praenatalis major ultrahangeltérése a facialis dysmorphismus volt. A teljes kromoszómaszerelvényt vizsgáló praenatalis tesztelés a ritka kromoszómaeltérések 12 lepényi mozaikos esetében (44%) feltételezhetően álpozitív, 1 esetben (3,7%) álnegatív eredményt generált volna, miközben a ritka autoszomális trisomiák 2 esetében ultrahangeltérés nélkül is korán detektálta volna a ritka magzati kromoszómaeltérést (7,4%). Következtetés: A normális tarkóredő-vastagság esetén észlelt major ultrahangeltérések felhívhatják a figyelmet a döntően mozaikos ritka kromoszóma-rendellenességekre. A teljes kromoszómaszerelvényt vizsgáló, nem invazív szűrőteszt a korai diagnosztika alternatívája lehet, a mozaikosságból adódó álpozitív eredményekre azonban számítani kell. A fetoplacentaris mozaikosság ismerete fontos klinikai információt biztosít, mely befolyásolhatja a terhesség kimenetelét, a terhesség követésének módját. A pontos citogenetikai karakterizálás elengedhetetlen. Orv Hetil. 2021; 162(29): 1156–1165. Summary. Introduction and objective: To determine the prevalence of microscopically visible de novo atypical chromosomal aberrations and fetoplacental mosaicism in a prenatal tertial referral center, and to investigate the maternal and fetal characteristics in connection with genomewide non-invasive prenatal screening. Method: Retrospective cohort study from 2014 to 2019 of pregnancies with invasive genetic analysis. Results: In the cohort of 2504 cases, the proportion of CVS was 53.3%. We diagnosed 200 chromosomal aberrations (8%), including 13.5% of de novo rare chromosomal aberrations (14 rare autosomal trisomies, 6 polyploidies, 5 structural aberrations and 2 small supernumerary marker chromosomes). The rate of fetoplacental mosaicism was 12.4%/77.8% in common/atypical chromosomal aberrations (p = 0.001) and confined to placenta in 17/40 cases. Associated ultrasound abnormalities were abnormal nuchal translucency and major malformations in 58% and 35% with common trisomies and 11% (p = 0.006) and 67% (p = 0.047) with true mosaic cases of rare abnormalities, respectively. Major ultrasound malformation was facial dysmorphism with rare aberrations. Potential application of genomewide non-invasive prenatal test in atypical chromosomal aberrations presumably would have been false-positive in 12 cases (44%), false-negative in 1 case (3.7%), and would have early detected 2 cases of rare autosomal trisomies (7.4%) without ultrasound anomalies. Conclusion: Structural ultrasound malformations with normal nuchal translucency thickness may be indicative of rare chromosomal aberrations. Application of genomewide non-invasive prenatal test is an alternative of early diagnostic methods with a potential of discordant results due to mosaicism. Knowledge about the presence of fetoplacental mosaicism influences risk estimation and genetic counseling, detailed cytogenetic characterization is of utmost importance. Orv Hetil. 2021; 162(29): 1156–1165.

Fetal fraction of free-DNA: clinical-diagnostic parallels

Introduction. Since 2011, a technology such as a non-invasive prenatal test (NIPT) has been used in the world i order o identify pregnant women at a high risk of giving birth to a child with chromosomal aneuploidy (CA). An important indicator of the test's effectiveness is the fetal fraction (FF), since its low level does not allow to give a reliable result to a patient.Aims: to determine the factors that can affect the level of FF during NIPT.Materials and methods. A retrospective comparative covenant study was carried out. The study included 288 patients who underwent NIPT in 2015-2018 after the standard complex of prenatal diagnosis (t 12-18 weeks of pregnancy). We assessed the correlation of the FF level with various clinical and anamnestic parameters and with indicators of biochemical screening for the first trimester (PAPP-A and β-ХГЧ). A comparison was made in terms of the FF level during pregnancy with a favorable and unfavorable outcome.Results. The average FF level in patient where CA was detected in the fetus was 9.01 (5.4-11)%, in the absence of CA — 9.7 (6.5-11.95)%, the difference are not statistically significant (p = 0.37). In patients with a physiological course of pregnancy, this indicator was 10.07 (6.6-12.57)%, and in patients with a complicated course of pregnancy, it was significantly lower — 8.11 (5.35-11.29)% (p = 0.02). We also analyzed the presence of a correlation between the level of FF and fetal weight at term, but no statistically significant correlation was found (r=0.13). There is a statistically significant inverse relationship between the FF level d the age of the pregnant woman, the patient's weight and body mass index, the number of pregnancies in the anamnesis, as well as a direct relationship between the FF and the β-hCG level (in MoM).Conclusions. FF is an important parameter of NIPT. A sufficient level of FF not only indicates a high reliability of the result obtained during NIPT, but also increases the chances of a favorable pregnancy outcome. The level of FF can be influenced by a number of clinical and anamnestic characteristics of the patient (weight body mass index, age, obstetric history). Studies aimed at determining the level of FF in various physiological and pathological conditions during pregnancy seem promising and thanks to them, it is possible that new models for predicting pregnancy complications will subsequently be proposed.

Reflex single-gene non-invasive prenatal test significantly increases the cost-effectiveness of carrier screening

Objective: To evaluate whether adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care is clinically and economically beneficial. Method: A decision-analytic model was developed to compare reflex sgNIPT as first-line carrier screening to the traditional sequential carrier screening workflow (positive maternal carrier screen is followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and cost effectiveness between the two screening methods. Results: Reflex sgNIPT carrier screening detected 108 of 110 affected pregnancies per 100,000 births (sensitivity 98.5%). This is a 2.4-fold improvement compared to the traditional sequential carrier screening, which detected 46 of 110 affected pregnancies per 100,000 births (sensitivity 41.5%). The testing costs in reflex sgNIPT carrier screening to identify one affected birth were $ 0.65 million, reduced by 62% from $1.73 million in traditional sequential carrier screening. Adoption of reflex sgNIPT carrier screening translated to a cost savings of $90.6 million per 100,000 births. Conclusion: Using reflex sgNIPT as the first-line carrier screening method improved the detection of affected births by 2.4-fold and saved $906 in healthcare costs per pregnancy screened. A real-life experience will need to assess the clinical utility of carrier screen with reflex sgNIPT.