**3.2. Ultrasound screening**

Ultrasound examination represents a good tool for the detection of morphological abnormalities in fetuses with chromosomal aberrations. In aneuploidies we could identify structural defects and non-structural findings (sonographic markers). Sonographic markers of fetal aneuploidy (SMFAs) are insignificant by themselves because they are nonspecific and often transient [60]. The sensitivity of sonography for detecting these abnormalities varies with a number of factors: type of chromosomal abnormality, gestational age, quality of the sonography and the experience of the sonographer. During the first trimester only the SMFA could be identified in pregnancies with aneuploid fetuses. During the second trimester, major/structural abnormalities could be observed in 20% of fetuses with trisomy 21 and in the majority of fetuses with trisomies 18 and 13. By combining SMFA and structural defects, the sonography allows the identification of 50% of fetuses with trisomy 21, 80% of fetuses with trisomy 18 and 90% of fetuses with trisomy 13 [61, 62].

#### *3.2.1. First-trimester screening*

During the first trimester of pregnancy many sonographic markers of fetal aneuploidy were described, but the most used are nuchal translucency and nasal bone (NB). Also, some major congenital anomalies could be identified but usually such changes are diagnosed during the second trimester of pregnancy.

#### *3.2.1.1. Nuchal translucency*

Nuchal translucency (NT) was introduced in medical practice in the 1990s and it is the sonographic appearance of a subcutaneous collection of fluid in the region of fetal neck [63]. Using a fixed cut-off for the NT measurement of 3 mm, it was possible to identify 64% of chromosomally abnormal cases, while only 4.1% of normal fetuses showed similar NT values [64]. It was proved that cut-off value was variable depending on gestational age, and it developed a Gaussian model for the NT variable that allowed this test to be readily combined with other markers [65].

an independent variation in relation with tricuspid regurgitation and by combining all these parameters it would be expected to achieve a detection rate of 95% at a 5% false positive rate

Prenatal Biochemical and Ultrasound Markers in Chromosomal Anomalies

http://dx.doi.org/10.5772/intechopen.73604

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Borrell et al. measured the pulsatility index for veins and found an abnormal blood flow through the ductus venosus (DV) in the Down fetus. \*\*\*They indicated that with a 4–5% false positive rate, the detection rate for trisomy 21 is 65–75%. The use of this marker in association with NT increased the detection rate to 75–80%. Combining these two markers with serum biochemical markers measured at 10 weeks provided a detection rate of 92% at a 5% false

Abele et al. analyzed retrospectively the NB, TR and DV. For normal children NB was identified in 2.0% of cases, TR was identified in 1.7% of cases and DV was identified in 3.5% of cases. In opposition, in cases with trisomy 21, NB was identified in 61.3% of cases, TR was identified in 61.3% of cases and DV was identified in 60.2% of cases. The normal children presented at least one of the markers in 5.9% of cases while more than 95% of the fetuses with trisomy 21 presented minimum 1 of these markers. The use of such combined prenatal screening (maternal age + NT + NB + TR + DV) during the first trimester could offer a detection rate of 95% with

The assessment of each of these ultrasound markers can be incorporated into first-trimester combined screening by maternal age, fetal NT and serum-free ß-hCG and PAPP-A, resulting in the improvement of the performance of screening with an increase in detection rate from

During the second trimester of pregnancy different sonographic markers could be identified, as well as major congenital anomalies. The most common markers in the second trimester are nuchal thickening, hyperechoic bowel, shortened extremities, renal pyelectasis, echogenic intracardiac foci (EIF) and choroid plexus cysts. The discovery of such a marker is important especially in cases with trisomy 21 because many cases with Down syndrome do not present major congenital anomalies. In other aneuploidies and also in triploidy, usually the visceral anomalies are common, and identification of a congenital defect imposes an invasive proce-

Trisomy 13 is a severe disorder, characterized by the presence of different malformations in the brain (holoprosencephaly, agenesis of the corpus callosum, Dandy-Walker malformation, vermian agenesis and neural tube defects), face (cyclopia, hypotelorism, cleft lip and palate), kidneys (renal cystic dysplasia and hydronephrosis) and heart (aterial septal defect, ventricular septal defect and patent ductus arteriosus). Also, cystic hygroma, polydactyly and club or rocker-bottom feet could be identified. All these anomalies can be observed easily by ultrasound examination in the second trimester of pregnancy. Also in the cases of trisomy 13 some sonographic markers can be discovered, but they are nonspecific. Such markers

or 90% at a 2% false positive rate [71].

1.5% false positive rate at a risk cut-off of 1:50 [73].

dure, followed by a chromosomal diagnosis [62].

*3.2.2. Second-trimester screening*

*3.2.2.1. Trisomy 13*

93 to 96% and a decrease in false positive rate to 2.5% [68, 71, 74].

positive rate [72].

The measurement of fetal NT thickness is done at the 11–14th week of gestation. This sonographic scan has been combined with maternal age to provide an effective method of screening for trisomy 21—at 5% false positive rate, about 75% of trisomic pregnancies can be identified by this method [63].

The explanations of NT are multiple but the most plausible are cardiovascular defects which cause over-perfusion of the head and neck and abnormal or delayed development of the lymphatic system. Thus, NT marker could be associated also with other chromosomal anomalies that produce fluid accumulation in the neck region. Also, NT can be a transient phenomenon that appears in a normal fetus and it spontaneously resolves in the second trimester [66].

#### *3.2.1.2. Nasal bone*

Cicero et al. were the first who evaluated the absence of the nasal bone (NB) in pregnancies and showed that it was present in 73% of trisomy 21 fetuses versus 0.5% of unaffected fetuses. They concluded that in trisomy 21, the absence of the nasal bone is not related to the nuchal translucency thickness, and thus both sonographic markers could be combined to provide an effective method of early screening for trisomy 21 [67]. This combined screening allows an increase of sensitivity from about 57 to 86% at a fixed false positive rate of about 1%. If the biochemical screening in the first trimester is added, a sensitivity of more than 90% could probably be achieved at a false positive rate of 1% [5, 67]. The analysis of nasal bone in aneuploidy versus euploidy, made by Kagan et al., showed that the nasal bone was absent in 2.6% of the euploid fetuses, in 59.8% with trisomy 21, 52.8% with trisomy 18, 45.0% with trisomy 13 and in none of the fetuses with Turner syndrome [68]. In contrast, Cicero et al. indicated that trisomy 21 was associated with the absence of nasal bone in 68.8% of cases, trisomy 18 in 54.8% of cases, trisomy 13 in 34.2% of cases, monosomy X in 10.9% of cases, gonosomal aneuploidies (XXX, XXY, XYY) in 5% of cases and other types of autosomal aneuploidies in 16.7% of cases, but none of the 19 cases with triploidy presented the absence of nasal bone [69].

#### *3.2.1.3. Other sonographic markers in the first trimester*

Another potential marker for trisomy 21 in the first trimester of pregnancy is tricuspid regurgitation (TR) observed by pulsed wave Doppler ultra-sonography. Falcon et al. indicated a tricuspid regurgitation in 67.5% of fetuses with trisomy 21, 33.3% of fetuses with trisomy 18 and only 4.4% of euploid fetuses [70]. Kagan et al. reported this anomaly in 55.5% of fetuses with trisomy 21, 33.3% of fetuses with trisomy 18, 30% of fetuses with trisomy 13, 37.5% of fetuses with monosomy X and only 0.9% of euploid fetuses. The free β-hCG and PAPP-A present an independent variation in relation with tricuspid regurgitation and by combining all these parameters it would be expected to achieve a detection rate of 95% at a 5% false positive rate or 90% at a 2% false positive rate [71].

Borrell et al. measured the pulsatility index for veins and found an abnormal blood flow through the ductus venosus (DV) in the Down fetus. \*\*\*They indicated that with a 4–5% false positive rate, the detection rate for trisomy 21 is 65–75%. The use of this marker in association with NT increased the detection rate to 75–80%. Combining these two markers with serum biochemical markers measured at 10 weeks provided a detection rate of 92% at a 5% false positive rate [72].

Abele et al. analyzed retrospectively the NB, TR and DV. For normal children NB was identified in 2.0% of cases, TR was identified in 1.7% of cases and DV was identified in 3.5% of cases. In opposition, in cases with trisomy 21, NB was identified in 61.3% of cases, TR was identified in 61.3% of cases and DV was identified in 60.2% of cases. The normal children presented at least one of the markers in 5.9% of cases while more than 95% of the fetuses with trisomy 21 presented minimum 1 of these markers. The use of such combined prenatal screening (maternal age + NT + NB + TR + DV) during the first trimester could offer a detection rate of 95% with 1.5% false positive rate at a risk cut-off of 1:50 [73].

The assessment of each of these ultrasound markers can be incorporated into first-trimester combined screening by maternal age, fetal NT and serum-free ß-hCG and PAPP-A, resulting in the improvement of the performance of screening with an increase in detection rate from 93 to 96% and a decrease in false positive rate to 2.5% [68, 71, 74].
