**5. Integration of NIPT into current prenatal care**

Although NIPT has just reached clinical application, the broad use of NIPT in high-risk and low-risk pregnancies is remarkable. Most professional societies have given recommendations to limit the application to women at higher risk [52–54], but the number of studies emerging from low risk and general populations are increasing and models for integration into health care plans are emerging.

A growing number of trials have now shown that NIPT can also be used in women at low risk for aneuploidy [19,27,31,33,55,56]. Although the positive predictive value is assumed to be lower in low-risk patients, test performance is still superior to conventional first trimester screening [27]. With a broad acceptance among specialist societies that a positive NIPT result requires confirmation by invasive testing, there seems to be no reason to withhold NIPT from low-risk women.

Basically, there are two discussed options: one is to use NIPT as a primary screening test that is offered to every pregnant woman and the second is to use NIPT as a secondary (contingent) screening test used only in certain risk groups. This could be either women of increased maternal age or women that screen positive in conventional screening. All discussed options refer to NIPT for trisomy 21,13, and 18 in singleton pregnancies as in traditional first trimester screening. All the other available NIPT options are not considered in a form of general clinical screening at this point.

A primary screening would lead to the highest detection rates of aneuploidies by lowering the false positive rates and also the need for invasive procedures [32]. However, the benefit of the first trimester ultrasound screening apart from aneuploidy detection needs to be remembered carefully since correct pregnancy dating by measuring crown-rump length is crucial for lowering perinatal mortality. Furthermore, the determination of twin chorionicity and an evaluation of maternal adnexae are part of the routine workup in the first trimester. Also, the majority of major fetal malformations that are not necessarily associated with genetic changes can be assessed by ultrasound. Further, primary screening also would be an expensive option by neglecting other benefits of first trimester ultrasound.

Considering contingent screening makes more sense from a healthcare point of view.

Since first trimester screening is widely used in many countries, it would make sense to offer NIPT to a selected population which is screen positive after first trimester screening. Such an approach was modeled with a test positive cut-off of 1:2,500 by first trimester screening and showed an increase of the detection rate of Down Syndrome with a decrease of invasive testing [57] at considerably lower costs compared to first-line screening.

In cases of a positive result, there is consensus among the specialist societies such as the American College of Obstetricians and Gynecologists (ACOG), the Society of Maternal-Fetal Medicine (SMFM), the International Society of Prenatal Diagnosis and the National Society of Genetic counselors that they need to be confirmed with an invasive procedure and fetal karyotyping. This seems especially important when a termination of pregnancy is considered following a positive NIPT result. As discussed previously, this is mandatory due to the occasional false-positive results, especially in low-risk patients.

Switzerland is the first country in Europe to have introduced a national policy on obligatory health care coverage for NIPT for women with singleton pregnancies that have a risk of > 1:1,000 for trisomy 21, 13, or 18 after conventional first trimester screening.
