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PONE-D-23-33164The implementation and impact of non-invasive prenatal testing (NIPT) for Down’s syndrome into antenatal screening programmes: a systematic review and meta-analysisPLOS ONE

Dear Dr. Sebire,

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Reviewer #1: Partly

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: In the field of fetal DNA floating in maternal peripheral blood, the acronym NIPT has to be indicated at least once as cffDNA-NIPT in papers where various non-invasive testing methods are analyzed. The described background of this paper is the basis of all global government programs for the reduction of invasive genetic diagnosis for Down syndrome. In such global scenario the data evaluation criteria must include also the ethnic, legal and ethical differences that strongly influence the application of the tests and the decision-making aspect of the pregnant woman. The quantitative amount of the case-sample used for the analysis must be presented in the text with the numerical values of the cases alongside the percentages, referring only the details to the tables. The decision of the pregnant women in terms of therapeutic abortion or DS livebirts is not relevant for the aim of the study, so the number of abortions and affected births cannot be the subject of meta-analysis but only of analytical and documented description by patient's age, gestation period, legal regulations of the country. The data of 27 selected papers, a small number, is more eligible for a traditional review than a meta-analysis, to be able to appreciate and not lose specific characteristics of each study. The great amount of limitations of the study described by the authors in their conclusions demonstrates that the meta-analysis does not allow to produce added value to the study exceeding some intuitive practical conclusions.

Reviewer #2: In this study the authors do a systematic review to understand the extent of NIPT introduction for Down’s syndrome into national screening programmes worldwide, its uptake among eligibile populations and the impact it may have on specific pregnancy outcomes.

As reported by the authors themselves, this review has many limitantions because many studies used for the meta-analyses do not report all the data necessary to analyse the outcomes of interest.

Furthermore, the paper has some points to be reviewed.

1. Some points regarding NIPT need to be corrected:

- DNA sequencing methods are not the only technologies used in non-invasive prenatal testing (lane 12-13), there are other technologies such as microarrays, nanofiltration plates with fluorescence scanning, Droplet

Digital PCR (ddPCR)

- re-evaluate literature reference 6 in lane 58;

- false-positive cases may be indicative of placental mosaicism, missing twins and "presence of maternal chromosomal abnormalities", the latter condition may be suggestive of maternal cancer, but not only (lane 71).

2. In Figure 2 and in the text, the authors do not explain all the reasons why 125 studies out of 167 were excluded from the review (30 are excluded due to 'unsuitable study population', 42 due to 'experimental study design' and the remaining 53?).

3. In Table 3, the authors refer to the Gadsboll et al. 2020 paper, but do not detail the situation in the individual countries reported as they should. For example, in Italy there are official guidelines supporting the use of NIPT in high-risk women already before 2019, but only some regions, such as Tuscany or Apulia, currently reimburse the test.

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Reviewer #1: No

Reviewer #2: No

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The implementation and impact of non-invasive prenatal testing (NIPT) for Down’s syndrome into antenatal screening programmes: a systematic review and meta-analysis

PONE-D-23-33164R1

Dear Dr. Sebire,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Giuseppe Novelli

Academic Editor

PLOS ONE

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