News in first trimester screening - can NIPT replace early combined screening?

Abstract

Effective screening for chromosomal abnormalities can be performed in the first trimester of pregnancy.
Chromosomal abnormalities occur in approximately 1 in 150 live births. Their incidence increases with age, but they can affect fetuses of pregnant women of any age (1).
Prenatal genetic screening, consisting of biochemical serum screening with ultrasound measurement of nuchal translucency (NT) or noninvasive prenatal testing (NIPT) based on circulating free DNA (cfDNA), and diagnostic testing (chorionic villus sampling or amniocentesis) as options, should be part of routine prenatal counseling and offered to all pregnant women, regardless of their age or risk for chromosomal abnormalities (1).
It is important to emphasize the distinction between a screening test that classifies patients at higher or lower risk for a specific fetal aneuploidy, versus a diagnostic test that diagnoses or excludes fetal chromosomal abnormalities, with the limitations of each chosen test.
Early detection of pregnancies at high risk for trisomies 21, 18, and 13 is the primary goal of prenatal screening for aneuploidy (2).
Early combined screening (ECS) involves ultrasound examination, i.e. measurement of nuchal translucency (NT) and determination of biochemical markers associated with aneuploidy: pregnancy-associated plasma protein A (PAPP-A) and free-beta or total human chorionic gonadotropin (hCG) secreted by the placenta.
Nuchal translucency is an ultrasound image of the collection of fluid between the skin and soft tissue covering the fetal spine at the back of the fetal neck. NT thickening is measured by ultrasound examination when the fetal crown-rump length (CRL) is 45 to 84 mm, corresponding to approximately 11+0 to 13+6 weeks of gestation. Fetuses with chromosomal abnormalities, cardiac defects, and many genetic syndromes have increased NT thickness (3).
Isolated ultrasound measurement of NT can detect 80% of fetuses with trisomy 21 and other major aneuploidies, with a false positive rate of 5%. The combination of NT and the biochemical markers of free β-hCG and PAPP-A improves the potential sensitivity to 90%. There is now evidence that the detection rate can be increased to about 95%, with a reduction in the false positive rate to 3%, by simultaneous examination of "new ultrasound markers": nasal bone, flow in the ductus venosus and tricuspid valve (4).
 The quality of NT measurement, as a marker for early screening, is extremely important, but is not consistent from study to study, probably due to variability in the expertise of the sonographer and the dependence on the quality of the equipment (5). For this reason, proper education and relicensing of persons, techniques and laboratories that perform early combined screening is necessary (5). The Fetal Medicine Foundation (FMF) provides education and quality assurance for ultrasound markers of aneuploidy.
The best interpretation of NT is within the framework of early combined screening that includes maternal age and first trimester biochemical markers, and the findings indicate the patient's specific risk for trisomy 21, 18, and 13 (6).
Down syndrome (T21) is the most common chromosomal abnormality among liveborn children. Pregnancies affected by Down syndrome are characterized by elevated biochemical markers beta-hCG, low PAPP-A, and elevated NT.
Trisomy 18 (T18) has a prevalence of 1 in 4000 births (7) and, as with trisomy 21, the incidence increases with advancing maternal age. The prevalence is 3-5 times higher in the first and second trimesters than at birth because many affected fetuses die spontaneously in utero. The early combined test shows a biochemical pattern characteristic of T18 in the first trimester: very low beta-hCG, very low PAPP-A, and increased nuchal translucency. Trisomy 13 is even more severe and rarer than trisomy 18, with a prevalence of approximately 1 in 7000 live births (7) and has biochemical and ultrasound markers similar to trisomy 18.
NT is not the only marker for trisomy 21, but approximately 50% of various chromosomal abnormalities are associated with elevated NT (6). Several perinatal scientific societies recommend invasive testing instead of NIPT when NT thickening is greater than the threshold of 3.0 mm or 3.5 mm (8).
Ultrasound examination in the first trimester from 11 to 13+6 weeks of pregnancy, in addition to determining the exact gestational age and measuring NT values, is also important for the first detailed examination of fetal morphology and the detection of various structural anomalies (8).
The introduction of non-invasive prenatal testing (NIPT) has reshaped the performance of prenatal early screening (8). Over the past decade, non-invasive prenatal testing has dramatically improved prenatal care, reducing the use and risks associated with invasive procedures such as amniocentesis and chorionic villus sampling (9).
Advances in genomics and related technologies have resulted in the development of non-invasive prenatal testing using fetal DNA sequences isolated from a maternal blood sample. NIPT provides direct insight into the fetal genotype through a new