**6. Influence of NIPT on diagnostic procedures and changes in prenatal care**

With the introduction of clinical available NIPT for the most common aneuploidies, a risk-free additional option of prenatal testing has become available. So far, most pregnant women in the western world had access to a detailed sonographic examination of the fetal anatomy (Figures 1 and 2), correct pregnancy dating based on Crown rump length at 11–14 weeks, and were offered the "combined first trimester test", which is a risk assessment for the trisomy 21, 13, and 18. The first trimester screening combines the statistical background risk of the mother incorporating her age, fetal anatomical markers, nuchal translucency measurements, and biochemical markers in maternal blood (pregnancy associated plasma–protein–A (PAPP-A) and free beta human chorionic gonadotropin (HCG). With this, aneuploidy screening for trisomy 21 can be achieved with a sensitivity of 90% at a false positive rate of 5% [58]. Women at increased risk would usually undergo an invasive procedure such as amniocentesis or chorionic villous sampling for karyotyping. Although this type of screening was better than any previous serum marker tests or using the maternal age-risk alone, it still lead to a large number of invasive tests and only few positive results. Putting mothers through an invasive procedure exposes them to a risk of fetal loss of 0.5–1% [59,60].

(Archive Dr. G. Manegold-Brauer, University of Basel, Department of Prenatal Medicine and Gynecologic Ultrasound)

**Figure 1.** 4D-ultrasound image of a fetus in the first trimester

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

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

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

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

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 >

**6. Influence of NIPT on diagnostic procedures and changes in prenatal care**

With the introduction of clinical available NIPT for the most common aneuploidies, a risk-free additional option of prenatal testing has become available. So far, most pregnant women in the western world had access to a detailed sonographic examination of the fetal anatomy (Figures 1 and 2), correct pregnancy dating based on Crown rump length at 11–14 weeks, and were offered the "combined first trimester test", which is a risk assessment for the trisomy 21, 13, and 18. The first trimester screening combines the statistical background risk of the mother incorporating her age, fetal anatomical markers, nuchal translucency measurements, and biochemical markers in maternal blood (pregnancy associated plasma–protein–A (PAPP-A) and free beta human chorionic gonadotropin (HCG). With this, aneuploidy screening for

screening at this point.

by neglecting other benefits of first trimester ultrasound.

416 Next Generation Sequencing - Advances, Applications and Challenges

[57] at considerably lower costs compared to first-line screening.

occasional false-positive results, especially in low-risk patients.

1:1,000 for trisomy 21, 13, or 18 after conventional first trimester screening.

With NIPT a new technology was introduced, which has lead to changes in algorithms previously used to guide patients. Since NIPT only requires a fetal blood sample, patients report that the greatest benefit is the decreased rate of miscarriage as compared to amniocent‐ esis or chorionic villous sampling [61,62].

The medical profession rapidly had to face and solve many challenges on offering and counseling patients about NIPT. It is especially challenging to distinguish scientific informa‐ tion on the different NIPT tests from commercial announcements due to the many different laboratories that offer these tests and the flood of published studies that emerged in only a few years. Adequate counseling has become very complex and should incorporate all the options,

**Figure 2.** 2D-ultrasound image of a fetal profile at 11–14 gestational weeks

limitations, and risks for each type of prenatal testing (ultrasound screening, biochemical screening, invasive procedures, NIPT, conventional karyotyping, and microarray analysis) in a non-directive manner and in the end should allow pregnant women to make an informed decision. For NIPT, it seems important to also counsel on non-reporting due to low fetal fraction in correlation to maternal weight and gestational age and fetal karyotype [63]. Further patients need to be informed on the need for an invasive procedure for confirmation in cases of positive findings.

However, in clinical practice the changes in prenatal care were incorporated differently in different health care systems and were highly dependent on the cohort that was investigated. The high costs associated with NIPT might also have played a role in the uptake in different societies. The introduction of NIPT has lead to an increased rate of prenatal testing in general. Many women that might have relied on first trimester screening in the past would now choose NIPT even if the results of first trimester screening were normal (Table 1). Not surprisingly, the increase of additional testing in the intermediate-risk group was most significant [64,65]. While the total number of invasive testing decreased by 70% in some studies [65], the reduction of invasive procedures was not significant in high-risk cohorts, especially when there is a high percentage of patients that present with anomalies seen on prenatal ultrasound. This man‐ agement, however, is comprehensible since there is a high risk of chromosomal anomalies other than trisomy 21, 13, and 18 when ultrasound anomalies are present (about one third) that


would not necessarily be picked up by NIPT but which can be detected by conventional karyotyping or microarray analysis.

**Table 1.** Differences in prenatal testing according to risk category before and after the introduction of NIPT. Group 1: before the introduction of NIPT, group 2: after the introduction of NIPT (adapted from [63]) IPT: invasive prenatal testing; *p*: *p*-value comparison before and after the introduction of NIPT, significant differences are marked with \*


IPT: invasive prenatal testing; NIPT: non-invasive prenatal testing.

Data shows number (%).

limitations, and risks for each type of prenatal testing (ultrasound screening, biochemical screening, invasive procedures, NIPT, conventional karyotyping, and microarray analysis) in a non-directive manner and in the end should allow pregnant women to make an informed decision. For NIPT, it seems important to also counsel on non-reporting due to low fetal fraction in correlation to maternal weight and gestational age and fetal karyotype [63]. Further patients need to be informed on the need for an invasive procedure for confirmation in cases

(Archive Dr. G. Manegold-Brauer, University of Basel, Department of Prenatal Medicine and Gynecologic Ultrasound)

**Figure 2.** 2D-ultrasound image of a fetal profile at 11–14 gestational weeks

418 Next Generation Sequencing - Advances, Applications and Challenges

However, in clinical practice the changes in prenatal care were incorporated differently in different health care systems and were highly dependent on the cohort that was investigated. The high costs associated with NIPT might also have played a role in the uptake in different societies. The introduction of NIPT has lead to an increased rate of prenatal testing in general. Many women that might have relied on first trimester screening in the past would now choose NIPT even if the results of first trimester screening were normal (Table 1). Not surprisingly, the increase of additional testing in the intermediate-risk group was most significant [64,65]. While the total number of invasive testing decreased by 70% in some studies [65], the reduction of invasive procedures was not significant in high-risk cohorts, especially when there is a high percentage of patients that present with anomalies seen on prenatal ultrasound. This man‐ agement, however, is comprehensible since there is a high risk of chromosomal anomalies other than trisomy 21, 13, and 18 when ultrasound anomalies are present (about one third) that

of positive findings.

**Table 2.** Management choices among high-risk patients after the introduction of NIPT. This table shows the presence or absence of sonographic findings (normal scan) in the high-risk group (*n* = 182) and management choices in the individual subgroups (adapted from [62]).
