1. Introduction

The history of early prenatal screening is a fascinating journey of medical achievements and technological advances aimed at identifying possible chromosomal abnormalities and other congenital diseases in the fetus, allowing expecting parents and doctors to prepare for possible problems in advance [1].

The rapid development of prenatal screening occurred in the mid-20th century with the advent of ultrasound. The founder was Ian Donald, who first used ultrasound to visualize the fetus and diagnose abnormalities, albeit only in the form of static images [2].

By the 1970s, thanks to the advent of real-time observation of fetal movements, ultrasound had already become the standard for prenatal diagnostics of fetal pathologies and developmental abnormalities [3].

The measurement of nuchal translucency (NT) began at 11-14 weeks of gestation, and its diagnostic value was proven in the 1990s in terms of increasing the risk of the following pathologies: Down syndrome (DS), Patau syndrome (PS), Edwards syndrome (ES), Turner syndrome, which in turn led to the widespread use of this method in combined first trimester screening [4].

The main purpose of NT measurement is to determine the risk of chromosomal abnormalities (CA) and congenital malformations (CM) in the fetus. Currently, NT screening detects 66.7-92% of CA and CM in early gestation and significantly improves the diagnostic quality of prenatal screening [4].

In the 1990s, along with NT determination by ultrasound, the detection of biochemical markers—free beta-human chorionic gonadotropin (β-hCG) and free unconjugated estriol (uE3)—as well as the pregnancy-associated AFP test (α-fetoprotein) associated with pregnancy, led to a significant increase in the accuracy of diagnosing chromosomal abnormalities [5].

Modern first trimester prenatal diagnostics is an integral part of obstetric dynamic monitoring, represented by several programs, one of which is Astraia Obstetrics (Astraia software gmbH, Germany), developed relatively recently with the support of the FMF (Fetal Medicine Foundation – FMF) (London, UK), which has undergone several clinical trials on a large number of pregnant women in different countries and is constantly being optimized [6]. According to the “Astraia Obstetrics” program, pregnant women with a risk of 1 ≤ 101 are classified as low risk, while those with a probability of 1 ≥100 are classified as high risk [6].

Another leap forward in prenatal screening took place at the turn of the millennium with the advent of non-invasive prenatal testing (NIPT), which is ten times more efficient than conventional biochemical screening. It can be performed before biochemical screening and before the end of pregnancy, but it has almost 100% sensitivity only for Down syndrome; for other chromosomal abnormalities - 92-97%, while the 99% accuracy of NIPT is a population indicator, and not an individual test accuracy [7].

The aim of the study was to conduct a comparative analysis of the diagnostic efficiency of the “Astraia Obstetrics” combined first trimester prenatal screening program in pregnant women with high and medium risk of fetal chromosomal abnormalities in comparison with non-invasive prenatal testing.

2. Material and Methods

Clinical observations were carried out at the Maternal and Child Diagnostic Center “Aliev`s Family” in Tashkent, where 46 pregnant women were examined in the period 2022-2024 after receiving the results of comprehensive prenatal screening under the Astraia Obstetrics program. The age of the patients was 26-38 years (mean age – 32.8±3.89 years) at a period of 11-13^{+6 days} weeks with a crown-rump length (CRL) of the fetus of 45-84 mm.

The following research methods were used in our study:

• instrumental examination methods (ultrasound with fetal fetometry and Doppler ultrasound of the venous duct and tricuspid valve of the fetal heart);

• results of the prenatal screening program "Astraia Obstetrics";

• NIPT;

• invasive prenatal diagnostics (IPD) (amniocentesis) to determine the karyotype of the fetus using the fluorescence in situ hybridization (FISH) method;

• statistical methods for processing the obtained research results.

3. Results

Ultrasound fetometry of the fetus performed by the transabdominal method at 11-13^+6days weeks of gestation in the pregnant women studied allowed us to confirm singleton pregnancy in all cases and various deviations from the norm according to many indicators (Tab. 1).

Table 1. Fetal biometry measurements of the patients studied (M±σ)

The mean NT thickness values of the fetuses statistically significantly exceeded the norms (P≤0.05) and averaged 2.96±0.56 mm, which indirectly indicated the presence of CA in the fetuses of the studied pregnant women. We also assessed the frequency of occurrence of NT thickness at 11-13^+6days weeks of gestation, exceeding the norm: this indicator was observed in 21 (45.65%) cases. Lack of visualization of the nasal bone was detected in the fetuses of 12 (26.09%) patients. In 7 (15.22%) fetuses we detected tricuspid regurgitation on ultrasound, which indicated the possible presence of congenital heart defects (CHD). The pulsatility index (PI) of blood flow in the venous duct above the norm was noted in 9 (19.57%) fetuses.

To unify prenatal screening programs, it is customary to use the MoM value - the ratio of the obtained absolute value of the marker to the median [8]. It should be taken into account that a shift in the median of one marker by 10% of the increase in risk rises the high-risk group by 1–2%, and a shift in the medians of several indicators leads to a shift corresponding to the total changes in the medians of the indicators [9].

The biochemical analysis of the content of pregnancy-associated proteins in the blood serum of patients within the framework of combined prenatal screening programs for the first trimester of pregnancy allowed us to conclude that the average concentration of PAPP-A was 0.67±0.11 mU/l (0.43±0.07 MoM), and the level of human chorionic gonadotropin β (hCG) was 156.3±20.6 ng/ml (2.18±0.4 MoM). Taking into account the serum concentrations of PAPP-A and βhCG in the pregnant women studied and the ultrasound markers of fetal CA development, the study group was divided by risk level into high (≥1:100) and above-medium (1:101–1:1000) based on the results of prenatal screening “Astraia”.

Thus, the high-risk subgroup according to the results of the comprehensive prenatal screening “Astraia Obstetrics” included 25 (54.35%) patients with a medium risk of 1: 89.16±6.37, and the above-medium risk subgroup included 21 (45.65%) pregnant women with a medium risk of 1: 658.37±117.82.

In high-risk subgroups, all patients underwent non-invasive prenatal testing (NIPT) and, regardless of its results, invasive prenatal diagnostics (IPD) by amniocentesis with determination of the fetal karyotype (FISH) were performed. In the intermediate risk subgroups, IPD was performed in patients with a high risk of developing CA according to the NIPT results.

In the high-risk subgroup of the study group, according to the results of the comprehensive prenatal screening "Astraia Obstetrics", a high risk of developing Down syndrome (DS) in the fetus was detected in 21 of 25 (84% of the subgroup) patients with a medium risk of 1: 87.21±7.86, and in the above-medium risk subgroup - in 20 of 21 (95.24%) pregnant women with a medium risk of 1: 649.18±113.82.

According to the NIPT results, 20 (86.96%) of 23 high-risk pregnant women had a high risk of developing DS (1: 89.13±9.15 on average), and 22 of 23 (95.65%) patients in the above-medium risk subgroup had a risk of developing DS (1: 746.15±127.41 on average) (Tab. 2).

Table 2. Risk levels for the development of CA in fetuses according to the “Astraia” program and NIPT

As for Edwards syndrome (ES), in the high-risk subgroup according to the results of prenatal screening, this CA accounted for 3 (12%) patients with a medium risk of 1: 97.21±1.79. In the above-medium risk group, 1 (4.76%) patient was identified with a risk of 1:676.

When studying the risk of ES in the high-risk subgroup according to the results of NIPT, this chromosomal abnormality accounted for 2 (8.7%) cases with a medium risk of 1: 98.14±1.62. In the above-medium risk group 1 (4,35%) patient was revealed with a risk of 1:714.

The risk of Patau syndrome (PS) developing in the high-risk subgroup according to the results of prenatal screening was detected in 1 (4%) pregnant woman with a risk of 1:96. There were no such cases in the above-medium risk group. According to the results of NIPT in the high-risk subgroup, the risk of PS was established in the same 1 (4.35%) pregnant woman with a risk of 1:98. There were no such cases in the above-medium risk group (Tab. 3).

Table 3. Comparative analysis of the CA developing risk according to the “Astraia” program, NIPT and IPD with FISH

Thus, we have established some difference between the results of determining the risk level according to the prenatal screening program “Astraia” and NIPT, subsequently, after conducting IPD amniocentesis with FISH, in both risk groups we determined the presence of CA development. So, the sensitivity of “Astraia Obstetrics” at high risk was 96.06% with a specificity of 96.1%, i.e. the diagnostic accuracy at high risk was 96.08%. For above-medium risk, this prenatal screening program had a sensitivity of 87.52% with a specificity of 88.4%, i.e. the diagnostic accuracy for above-medium risk made up 87.96%.

NIPT has a sensitivity of 98.24% in the high-risk group with a specificity of 98.2%, and the diagnostic accuracy was 98.22% (Fig. 1).

Figure 1. Diagnostic indicators of the "Astraia" prenatal screening program and NIPT in the high-risk group, %

In the above-medium risk group, the sensitivity of NIPT was 95.42% with a specificity of 95.1% and a diagnostic accuracy of 95.26% (Fig. 2).

Figure 2. Diagnostic indicators of the "Astraia" prenatal screening program and NIPT in the above-medium group, %

4. Conclusions

It is possible to determine the risk level of fetal chromosomal abnormalities (CA) with high probability by using NIPT at the primary diagnostic stage before or in parallel with FISH results, especially Down syndrome (DS) in women of any age up to 14 weeks. Regression analysis suggests that NIPT results can be used independently for screening the risk of developing fetal CA.

The diagnostic accuracy of NIPT for determining the risk of fetal CA development that we have established is an important contribution to the methodology of complex screening studies of pregnant women, especially those with two or more risk factors for this pathology and those located in remote areas, which will be useful for diagnosing CA in the practice of obstetricians and gynecologists.

Conflict of Interests’ Statement

The author declares no conflict of interest.

This study does not include the involvement of any budgetary, grant or other funds.

The article is published for the first time and is part of a scientific work.

ACKNOWLEDGEMENTS

The author expresses their gratitude to the management of the Maternal and Child Diagnostic Center “Aliev`s Family” for the material provided for our study.

Ethical Approval and Consent to Participate

The Research Ethics Board of our institution does not require review or approval of case reports. Our research was carried out in accordance with the World Medical Association Code of Ethics (Declaration of Helsinki).