MSAFP is also not perfectly sensitive, because its assessment depends on statistically defined cutoff values. If an elevated concentration is defined as two multiples of the median value in pregnancies without any abnormality that could raise the AFP concentration, one can estimate that 20% of fetuses with open NTDs remain undetected. However, lowering the cutoff to improve sensitivity would be at the expense of reduced specificity, thereby increasing the false-positive rate.
The combined use of the MSAFP assay with detailed diagnostic ultrasonography (see later discussion) approaches the accuracy of AFAFP assay and ultrasonography for the detection of open NTDs. Thus first-degree, second-degree, or more remote relatives of patients with NTDs may have an MSAFP assay (at 16 weeks) followed by detailed ultrasound examination (at 18 weeks) rather than undergoing amniocentesis.
Screening for Down Syndrome and Other Aneuploidies
More than 70% of all children with major autosomal trisomies are born to women who lack known risk factors, including advanced maternal age (see Fig. 6-1). A solution to this problem was first suggested by the unexpected finding that MSAFP concentration (measured, as just discussed, during the second trimester as a screening test for NTD) was depressed in many pregnancies later discovered to have an autosomal trisomy, particularly trisomies 18 and 21. MSAFP concentration alone has far too much overlap between unaffected pregnancies and Down syndrome pregnancies to be a useful screening tool on its own (see Fig. 17-5). However, a battery of maternal serum protein analytes has now been developed that in combination with specific ultrasound measurements has the necessary sensitivity and specificity to be useful for screening. These batteries of tests are now recommended for noninvasive screening, although not for definitive diagnosis, during the first and second trimesters of all pregnancies regardless of maternal age.
First-Trimester Screening
First-trimester screening is ideally performed between 11 and 13 weeks of gestation and relies on measuring the level of certain analytes in maternal serum in combination with a highly targeted ultrasonographic examination. The analytes used are pregnancy-associated plasma protein A (PAPP-A) and the hormone human chorionic gonadotropin (hCG), either as total hCG or as its free β subunit. PAPP-A is depressed below the normal range in all trisomies; hCG (or free β-hCG) is elevated in trisomy 21 but depressed in the other trisomies (Table 17-6). Analyte measurements are combined with ultrasonographic measurement of 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. An increase in NT is commonly seen in trisomies 21, 13, and 18 and in 45,X fetuses (Fig. 17-6). NT varies with age of the fetus and thus must be determined with reference to gestational age.
TABLE 17-6
Elevation and Depression of Parameters Used in First- and Second-Trimester Screening Tests
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