Although the association between advancing maternal age and increased risk for major trisomies is well known, more than 70% of children with autosomal trisomies are born to women without risk factors. The unexpected finding that the concentration of MSAFP, measured during the second trimester to screen for NTDs, was lower in women who carried pregnancies with autosomal trisomies, particularly trisomies 18 and 21, led to its investigation as a screening analyte for Down syndrome (trisomy 21); however, MSAFP concentrations of unaffected pregnancies and Down syndrome pregnancies overlap too much (see Fig. 1) for MSAFP to be a useful screening analyte on its own. Since then more sensitive and specific trisomy screening strategies have been developed that combine different serum analytes in the first or second trimester with specific ultrasound measurements. About 10 years ago analysis of cell- free DNA in maternal plasma was introduced. Cell- free DNA screening can be done at any gestational age after 10 weeks and is more sensitive and specific for aneuploidy screening than serum analyte screening. The most recent guidance states that all pregnant women should be informed about the option of cell- free DNA analysis along with other screening and testing, but the less costly serum analyte screening is still used for women at low or average risk for fetal aneuploidy. Thus all these different screening options will be explained in more detail later.

Fig1. Maternal serum α- fetoprotein (AFP) concentration, expressed as multiples of the median, in normal fetuses, fetuses with open neural tube defects, and fetuses with Down syndrome. (Redrawn from Wald NJ, Cuckle HS: Recent advances in screening for neural tube defects and Down syndrome. In Rodeck C, editor: Prenatal diagnosis, London, 1987, Bailliére Tindall, pp 649– 676.)

First Trimester Screening

First trimester screening is ideally performed between 11 and 13 completed weeks of gestation and relies on measuring the levels of pregnancy- associated plasma protein A (PAPP- A) and the hormone human chorionic gonadotropin (hCG), either as total hCG or as its free β subunit in maternal serum. PAPP- A levels are below the normal range in all trisomies; hCG (or free β- hCG) is higher in trisomy 21 but lower in the other trisomies (Table 1). These analyte measurements are combined with the ultra sonographic measurement of the nuchal translucency (NT), defined as the thickness of the echo- free space between the skin and the soft tissue overlying the dorsal aspect of the cervical spine caused by subcutaneous edema of the fetal neck (Fig. 2A). An increase in NT is commonly seen in fetuses with trisomies 21, 13, and 18 and in 45,X (see Fig. 2B). Sonographers performing NT measurements used for first trimester screening must obtain and maintain special certification, and the size must be determined with reference to gestational age. An enlarged NT in fetuses with a normal karyotype is associated with an increased risk for other genetic conditions and birth defects. The most common ones are listed in Table 2.

Table1. Performance of First and Second Trimester Screening Tests

Fig2. First trimester nuchal translucency (NT) measurements. The NT is a dark, echo- free zone beneath the skin in an ultrasonographic sagittal section through the fetus and is marked by two yellow “+” signs. The average NT size is 1.2 mm at 11 weeks of gestation (95th percentile up to 2 mm) and 1.5 mm at 14 weeks of gestation (95th percentile up to 2.6 mm). (A) Normal NT measurement of 1.25 mm. (B) Increased NT measurement associated with a greatly increased risk for Down syndrome. (Images courtesy of Wesley Lee, MD, Baylor College of Medicine, Houston, Texas.)

Table2. Common Causes of Increased Nuchal Translucency Thickness

Second Trimester Screening

 Second trimester screening for trisomies 21 and 18 is usually accomplished by measuring hCG levels in com bination with three other analytes: MSAFP, unconjugated estriol (uE3), and inhibin A. This battery of tests is referred to as a quadruple screen. MSAFP and uE3 are lower than average when the fetus has a trisomy 21 or 18, whereas hCG is higher with fetal trisomy 21 but lower with trisomy 18, and inhibin A is higher with fetal trisomy 21 but not significantly affected in trisomy 18 (see Table 18.2). These analyte levels are affected by other factors, including ancestry, smoking, maternal diabetes, multiple pregnancy, and pregnancy conceived by in vitro fertilization (IVF), and laboratories generally adjust for these variables. Extremely low levels of uE3 may be indicative of rare genetic conditions such as steroid sulfatase deficiency or Smith- Lemli- Opitz syndrome. Second trimester screening is generally reserved for low- risk patients who missed the window for first trimester screening. For standard first and second trimester screening a cutoff of screen positive rate of 5% results in the detection rates of first and second trimester screening shown in Table 1.

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مواضيع ذات صلة

The Origin and Frequency of Different Types of Mutation

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Neural Tube Defects

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer

Screening for Genetic Susceptibility to Disease

Pharmacogenomics

Monogenic Diseases Show One of Three Patterns of Inheritance

Tumor Suppressor Genes in Autosomal Dominant Cancer Syndromes

Activated Oncogenes in Hereditary Cancer Syndromes