**5. Conclusions**

such subtelomeric rearrangements. In the prenatal diagnosis, "targeted" arrays are commonly used, containing genomic clones for subtelomeric regions and those that are frequently involved in microdeletion/microduplication syndromes. The major advantage of array-CGH is the very high resolution, this technique allowing the detection of genomic changes of 50–100 kb. The main inconvenient is the possibility of detecting copy number variants (CNVs) with unknown clinical consequences. In this case, with limited possibility of fetal phenotype investigation, the evaluation of functional consequences of genomic changes is very difficult. A CNV discovered in these conditions is most probably pathogen if it is de novo, has a size >1 Mb, contains a deletion

Nowadays, in developed countries, the array-CGH represents the first option in the prenatal genetic investigation of fetuses with multiple congenital anomalies detected by ultra-sonography.

Each method used in prenatal screening has some inconvenients that can be limited by using a combination of multiple assays. Biochemical and ultrasound screening can be done at the same time or at different times. The first method is called concurrent and the second sequential. The sequential protocol can offer the results when all analyses are complete—non-disclo-

The biochemical screening in the first trimester is based on the detection of PAPP-A and ß-hCG. The PAPP-A has a different discriminatory power in a different week of gestation with a decline from the 10th to 13th week. For a predicted detection rate with 5% false positive rate the combination of PAPP-A and ß-hCG has a detection rate of 72% in 10th week, 65% in 11th week, 57% in 12th week and 51% in 13th week. By using a combination between double test (PAPP-A and ß-hCG) with detection of aFP and μE during second trimester, the detection rate increases to 78% (with PAPP-A measured in the 10th week), 72% (with PAPP-A measured in the 11th week), 66% (with PAPP-A measured in the 12th week) and 61% (with PAPP-A measured

Nuchal translucency (NT) is independent for gestational age and its screening can be done at 11–13 weeks, with a detection rate of 73% for a 5% false positive rate. By combining biochemical screening in the first trimester with sonographic examination, the detection rate can increase. The best solution is to apply the biochemical screening in weeks 10–12 and the sonographic examination 1 week later. Using this protocol, the detection rate is 92% with double test done in the 10th week, 89% with double test done in the 11th week and 87% with double test done in the 12th week [119].

The best results are obtained using a non-disclosure protocol that combined NT with double test in the first trimester and detection of aFP and μE in the second trimester. This test, called integrated test, generates a detection rate of 93% (with PAPP-A measured in the 10th week), 92% (with PAPP-A measured in the 11th week), 91% (with PAPP-A measured in the 12th week) and 90% (with PAPP-A measured in the 13th week) for a 5% false positive rate. The use of such an algorithm has the inconvenience of having to wait a long time because the final

sure method—or at the time when each analysis is finished—step-wise method [119].

rather than a duplication and involves a gene-rich area [116–118].

386 Congenital Anomalies - From the Embryo to the Neonate

**screening**

in 13th week) [119].

**4. The combined use of biochemical and ultrasound prenatal** 

The chromosomal disorders have an important impact on the health of future infants. For this reason, in the last decade, important efforts were made to improve the prenatal screening and diagnosis. The prenatal screening uses non-invasive methods that allow the detection of pregnancies with risk of chromosomal anomalies. These methods can be done in the first or second trimesters of pregnancy. The first-trimester screening methods are biochemical and sonographic. Biochemical screening for first trimester uses the detection of PAPP-A and β-hCG in the maternal serum. Sonographic examination in the first trimester allows the detection of some markers—nuchal translucency, absence of the nasal bone, tricuspid regurgitation or abnormal blood flow through the ductus venosus—that are associated with high risk for aneuploidy. The prenatal screening during the second trimester of pregnancy can be done by biochemical or sonographic examinations as well. The biochemical screening is based on the detection of aFP, hCG (or β-hCG), μE and inhibin A in maternal serum. The sonographic examinations in the second trimester can identify some structural defects (cardiac, cerebral, renal, etc.) but more frequent are the sonographic markers like nuchal thickening, hyperechoic bowel, shortened limbs, pyelectasis, echogenic intracardiac foci, widened pelvic angle, and so on. The best choice for prenatal screening of aneuploidies is the use of combined biochemical (in the first and second trimesters) and sonographic examination. Such protocol has a detection rate higher than 90% at 5% false positive rate. The prenatal diagnosis requires an invasive procedure (chorionic villus sampling, amniocentesis, cordocentesis) to obtain fetal material. The fetal cells can be used for cytogenetic or molecular analyses. The cytogenetic analyses (fetal karyotype) require a long-time cell culture and have a limited resolution but have the advantage of diagnosis of all chromosomal anomalies. Some molecular analyses (FISH, QF-PCR, MLPA) are targeted methods and can identify only specific anomalies, such as aneuploidies of chromosomes 21, 18, 13 X and Y. Array-CGH (molecular karyotype) eliminates the major inconvenience of karyotype (long-time culture and limited resolution) but is expensive and thus it's use remains prohibitive in countries with limited economical resources. However, the implementation of prenatal screening and diagnosis allows many couples the opportunity to take an informed decision in relation to their baby's future.
