TABLE 14-5. Positive-Predictive Value of Cell-Free DNA Screening for Autosomal Trisomies and Selected Sex Chromosome Abnormalities, According to Maternal Age
Maternal Age Trisomy 21 Trisomy 18 Trisomy 13 45,X 47,XXY
NA = not available; ��IPT = non-invasive prenatal test.
Positive-predictive values were obtained using the NIPT/Cel1 Free DNA Screening Predictive Value Calculator from the Perinatal Quality Foundation, 2017. Calculations are based on prevalence at 16 weeks' gestation using sensitivities and specificities from Gil, 2015.
low, the negative-predictive value of all aneuploidy screening tests generally exceeds 99 percent (Gil, 2015; Norton, 2015).
are also called conventional or traditional to diferentiate them from cell-free DNA-based screening. There are three categories: irst-trimester screens, second-trimester screens, and combina tions of irst-and second-trimester screens. If the test has a irst trimester component, it almost always includes a measurement of the sonographic nuchal translucency, which is discussed in the next section.
Each maternal serum analyte is measured as a concentration-for example, nanograms per milliliter of AFP. he concentration is converted to a multiple of the median (MoM) by adjusting for maternal age, maternal weight, and gestational age. he nuchal translucency measurement increases with crown-rump length (CRL) , and thus its value is adjusted for CRL and also reported as an MoM. The AFP analyte is further adjusted for maternal race and ethnicity and for presence of diabetes, which all afect the calculation of neural-tube defect risk rather than of aneuploidy risk (Greene, 1988; Huttly, 2004). Reporting these results as an MoM of the unafected population normalizes the distribution of analyte levels and permits comparison of results from diferent laboratories and populations.
he analyte-based aneuploidy screening result is based on a composite likelihood ratio, and the maternal age-related risk is multiplied by this ratio. his principle similarly applies to modiication of fetal Down syndrome risk by selected sonographic markers, which are discussed later on page 286. Each woman is provided with a speciic risk for trisomy 21 and for trisomy 18-or in the irst trimester, for trisomy 18 or 13 in some cases. he result is expressed as a ratio that represents the positive-prediCtive value.
Importantly, each screening test also has a predetermined value at which or above which it is deemed "positive" or abnormal. For second-trimester tests, this threshold has traditionally been set at the risk for fetal Down syndrome in a woman aged 35 years-approximately 1 in 270 in the second trimester (see Table 14-1). he threshold selected for a positive screen relects the laboratory requirement but is somewhat problematic, as it may bear no relationship to patient preference. However, a positive screening result may afect whether the patient is deemed "high risk," receives formal genetic counseling, and is ofered diagnostic testing with chorionic villus sampling or amniocentesis. Thus, it behooves the provider to discuss the patient's preferences prior to screening.
Also called combined irst-trimester screening, this test combines two maternal serum analytes, human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A), with the sonographic measurement of the nuchal translucency (NT). It is performed between 11 and 14 weeks' gestation. In cases of fetal Down syndrome, the irst-trimester serum free 3-hCG level is higher and the PAPP-A level is lower. With trisomy 18 and trisomy 13, levels of both analytes are lower (Cuckle, 2000; Malone, 2005b).