While tremendous advances have been made in recent years regarding screening for fetal aneuploidy in the first trimester of pregnancy, the mainstay of screening for aneuploidy has been second trimester serum and sonographic screening. Despite the increasing popularity of first trimester screening, there will always be a role for second trimester aneuploidy screening given that some patients do not present for antenatal care sufficiently early in pregnancy to avail of nuchal translucency and given that a second trimester fetal anatomical survey has become an almost routine aspect of general antenatal care. Additionally, since first trimester screening requires the availability of chorionic villus sampling (CVS) to provide a first trimester diagnosis, in areas in which CVS is not available there will be a continued requirement for second trimester screening protocols leading to amniocentesis.

Options for second trimester screening include serum screening using the Quad test (alphafetoprotein, human chorionic gonadotropin, unconjugated estriol, and inhibin-A), sonographic screening using the so-called Genetic Sonogram, and combinations of serum and sonographic screening.

Maternal serum levels of alphafetoprotein (AFP) and unconjugated estriol (uE3) are both approximately 25% lower in pregnancies complicated by Down syndrome, compared with euploid pregnancies (Wald et al., 1994; Malone et al., 2005). By contrast, levels of hCG and inhibin-A are approximately twice as high in pregnancies complicated by Down syndrome (Wald et al., 1994; Malone et al., 2005). Maternal serum levels of AFP, uE3, and hCG all tend to be decreased in pregnancies complicated by trisomy 18. The combination of AFP, uE3, and hCG, commonly known as the triple screen, can detect 69% of cases of Down syndrome, for a 5% false-positive rate (Wald et al., 2003; Malone et al., 2005). When inhibin-A is added to this test, commonly known as the Quad screen, the Down syndrome detection rate increases to 81%, for a 5% false-positive rate (Wald et al., 2003; Malone et al., 2005). Based on these results, if a second trimester serum sample is obtained for aneuploidy risk assessment, optimal performance will be obtained by measuring the four serum markers, rather than any double or triple marker combination.

Performance of serum screening tests can be maximized by accurate ascertainment of gestational age, and wherever possible, sonographic dating should be used instead of menstrual dating. It is optimal to provide serum screening between 15 and 16 weeks’ gestation, thereby allowing the results to be available at the time of second trimester sonographic evaluation. Subsequently, if this sonographic evaluation reveals any markers for aneuploidy, the Down syndrome risk quoted from serum screening can be used with the ultrasound findings to determine the most precise final Down syndrome risk. Adequate time should then be available for diagnostic genetic amniocentesis if indicated by the screening results.

Sonographic evaluation of the fetal anatomy at 18 weeks’ gestation has become a routine aspect of antenatal care in most developed countries. When this methodical evaluation for fetal malformations is used to assess the risk for fetal aneuploidy, the term Genetic Sonogram is commonly used. Risk for fetal aneuploidy can be assessed by the detection of either major structural malformations known to be associated with aneuploidy, or by the detection of a range of minor sonographic markers that increase the chances of fetal aneuploidy (Table 3-1).

The detection of certain major structural malformations that are known to be associated with aneuploidy should prompt an immediate consideration for genetic amniocentesis. Major structural malformations that are associated with Down syndrome include cardiac malformations (AV canal defect [Figure 3-1], ventricular septal defect, tetralogy of Fallot), duodenal atresia (Figure 3-2), cystic hygroma (Figure 3-3), and hydrops fetalis (see Chapter 131). The major malformations associated with trisomy 18 include cardiac malformations (AV canal defect, ventricular septal defect, double outlet right ventricle), meningomyelocele, omphalocele, esophageal atresia, rocker bottom feet, cleft lip or palate, cystic hygroma, and hydrops fetalis (see Chapter 130). While the Genetic Sonogram can be performed at any time during the second and third trimesters, the optimal time is likely to be at 17 to 18 weeks’ gestation, which is late enough to maximize fetal anatomical evaluation, yet early enough to allow for amniocentesis results to be obtained. When a major structural malformation is found, such as an AV canal defect or a double-bubble suggestive of duodenal atresia, the risk of Down syndrome in that pregnancy can be increased by approximately 20-to 30-fold (Nyberg et al., 1998). For almost all patients, such an increase in their background risk for aneuploidy will be sufficiently high to justify immediate genetic amniocentesis.

Second trimester sonography can also detect a range of minor markers for aneuploidy. The latter are not considered structural abnormalities of the fetus per se, but when noted, may be associated with an increased probability that the fetus is aneuploid. The minor markers that have been commonly linked to Down syndrome include nuchal fold thickening (Figure 3-4), nasal bone hypoplasia (Figure 3-5), mild ventriculomegaly, short femur or humerus, echogenic bowel (Figure 3-6), renal pyelectasis (Figure 3-7), echogenic intracardiac focus (Figure 3-8), clinodactyly (Figure 3-9), sandal gap toe (Figure 3-10), and widened iliac angle (Nyberg et al., 2001). The minor markers that are associated with trisomy 18 include nuchal fold thickening, mild ventriculomegaly, short femur or humerus, echogenic bowel, enlarged cisterna magna, choroid plexus cysts (Figure 3-11), micrognathia, single umbilical artery (Figure 3-12), clenched hands, and fetal growth restriction. It should be noted that almost all data supporting the role of second trimester sonography for minor markers for aneuploidy are derived from high-risk populations, such as patients of advanced maternal age or with abnormal maternal serum screening results. It is still unclear what the relative contribution of screening for such minor markers will be in lower risk patients from the general population.