At least 8 percent of conceptuses are aneuploid, accounting for 50 percent of first-trimester abortions and 5 to 7 percent of all stillbirths and neonatal deaths. As discussed in Chapter 13 (Chromosomal Abnormalities), the risk of fetal trisomy increases with maternal age, particularly after age 35. Specific maternal age-related aneuploidy risks for singleton and twin pregnancies are shown in Tables 14-3 and 14-4. Other significant risk factors include a prior pregnancy with autosomal trisomy or triploidy or a woman or her partner with a numerical chromosomal abnormality or structural chromosomal rearrangement, such as a balanced translocation.
TABLE 14-3Maternal Age-Related Risk for Down Syndrome and Any Aneuploidy at Midtrimester and at Term in Singleton Pregnancies ||Download (.pdf) TABLE 14-3 Maternal Age-Related Risk for Down Syndrome and Any Aneuploidy at Midtrimester and at Term in Singleton Pregnancies
| ||Down Syndrome ||Any Aneuploidy |
|Age ||Midtrimester ||Term ||Midtrimester ||Term |
|35 ||1/250 ||1/385 ||1/132 ||1/204 |
|36 ||1/192 ||1/303 ||1/105 ||1/167 |
|37 ||1/149 ||1/227 ||1/83 ||1/130 |
|38 ||1/115 ||1/175 ||1/65 ||1/103 |
|39 ||1/89 ||1/137 ||1/53 ||1/81 |
|40 ||1/69 ||1/106 ||1/40 ||1/63 |
|41 ||1/53 ||1/81 ||1/31 ||1/50 |
|42 ||1/41 ||1/64 ||1/25 ||1/39 |
|43 ||1/31 ||1/50 ||1/19 ||1/30 |
|44 ||1/25 ||1/38 ||1/15 ||1/24 |
|45 ||1/19 ||1/30 ||1/12 ||1/19 |
TABLE 14-4Maternal Age-Related Risk for Down Syndrome and Any Aneuploidy at Midtrimester and at Term in Dizygotic Twin Pregnanciesa ||Download (.pdf) TABLE 14-4 Maternal Age-Related Risk for Down Syndrome and Any Aneuploidy at Midtrimester and at Term in Dizygotic Twin Pregnanciesa
| ||Down Syndrome ||Any Aneuploidy |
|Age ||Midtrimester ||Term ||Midtrimester ||Term |
|32 ||1/256 ||1/409 ||1/149 ||1/171 |
|33 ||1/206 ||1/319 ||1/116 ||1/151 |
|34 ||1/160 ||1/257 ||1/91 ||1/126 |
|35 ||1/125 ||1/199 ||1/71 ||1/101 |
|36 ||1/98 ||1/153 ||1/56 ||1/82 |
|37 ||1/77 ||1/118 ||1/44 ||1/67 |
|38 ||1/60 ||1/92 ||1/35 ||1/54 |
|39 ||1/47 ||1/72 ||1/27 ||1/44 |
|40 ||1/37 ||1/56 ||1/21 ||1/35 |
|41 ||1/29 ||1/44 ||1/17 ||1/28 |
|42 ||1/23 ||1/33 ||1/13 ||1/22 |
Until the mid-1980s, prenatal diagnostic testing for fetal aneuploidy was offered for “advanced maternal age.” However, age alone is a poor screening test, because approximately 70 percent of Down syndrome pregnancies are in women younger than 35 years. Nearly 30 years ago, Merkatz and associates (1984) observed that pregnancies with Down syndrome were characterized by lower maternal serum AFP levels at 15 to 20 weeks, and screening became available for younger women. During the past two decades, there have been four major advances in the area of aneuploidy screening:
The addition of other serum analytes to second-trimester screening has improved Down syndrome detection rates to approximately 80 percent for the quadruple marker test (Table 14-5).
First-trimester screening at 11 to 14 weeks’ gestation, using the fetal nuchal translucency measurement together with serum analytes, has achieved Down syndrome detection rates comparable to those for second-trimester screening in women younger than 35 years (American College of Obstetricians and Gynecologists, 2013c).
Combinations of first- and second-trimester screening yield Down syndrome detection rates as high as 90 to 95 percent (Malone, 2005b).
Maternal serum cell-free fetal DNA testing for trisomy 21, 18, and 13 has become available as a screening test for high-risk pregnancies, with a 98-percent detection rate and a false-positive rate of 0.5 percent (American College of Obstetricians and Gynecologists, 2012b; Bianchi, 2012; Palomaki, 2011, 2012).
TABLE 14-5Selected Down Syndrome Screening Strategies and Their Detection Rate ||Download (.pdf) TABLE 14-5 Selected Down Syndrome Screening Strategies and Their Detection Rate
|Strategy ||Analytes ||Detection Ratea (%) |
|First-trimester screen |
|NT, PAPP-A, and hCG or free β-hCG |
|Triple test ||MSAFP, hCG or free β-hCG, uE3 ||61–70 |
|Quadruple (Quad) test ||MSAFP, hCG or free β-hCG, uE3, inh ||74–81 |
|Integrated screen ||First-trimester screen and Quad test; results withheld until Quad test completed ||94–96 |
|Stepwise sequential screen ||First-trimester screen and Quad test |
1% offered diagnostic test after first-trimester screen
99% proceed to Quad test, results withheld until Quad test completed
|Contingent sequential screen ||First-trimester screen and Quad test |
1% offered diagnostic test after first-trimester screen
15% proceed to Quad test; results withheld until Quad test completed
84% have no additional test after first-trimester screen
|Cell-free fetal DNA testing (high-risk pregnancies) ||No analytes—massively parallel genomic sequencing ||98 |
With the exception of cell-free fetal DNA testing, each first- and/or second-trimester aneuploidy screening test is based on a composite likelihood ratio, and the maternal age-related risk is multiplied by this ratio. This principle also applies to modification of the Down syndrome risk by selected sonographic findings (Sonographic Screening). Each woman is provided with a specific risk, expressed as a ratio—1:X. However, each screening test has a predetermined value at 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 385 at term (see Table 14-3). Women with a positive screening test result should be offered a diagnostic test for fetal karyotype by either chorionic villus sampling or amniocentesis (American College of Obstetricians and Gynecologists, 2012a).
Because technology advances have resulted in improved aneuploidy detection with available screening tests, the American College of Obstetricians and Gynecologists (2013c) recommends that all women who present for prenatal care before 20 weeks be offered screening. Available screening paradigms are shown in Table 14-5. A positive screening test result indicates increased risk, but it is not diagnostic of aneuploidy. Conversely, a negative screening test indicates that the risk is not increased, but it does not guarantee a normal fetus. Although Down syndrome is the focus of most aneuploidy screening protocols, it accounts for only half of all fetal chromosomal abnormality cases. Invasive diagnostic tests such as chorionic villus sampling and amniocentesis are safe and effective. Regardless of age, all women are counseled regarding the differences between screening and diagnostic tests, and they are given the option of invasive diagnostic testing.
The most commonly used protocol involves measurement of sonographic nuchal translucency and two maternal serum analytes. This is performed between 11 and 14 weeks’ gestation.
This is the maximum thickness of the subcutaneous translucent area between the skin and soft tissue overlying the fetal spine at the back of the neck (Fig. 14-5). It is measured in the sagittal plane, when the crown-rump length measures between 38 and 84 mm. Specific criteria for NT measurement are listed in Table 10-3 (Nuchal Translucency (NT)). The NT measurement is expressed as a multiple of the gestational age-specific median, similar to serum markers used for aneuploidy screening. An increased NT thickness itself is not a fetal abnormality, but rather is a marker that confers increased risk. Approximately one third of fetuses with increased nuchal translucency thickness will have a chromosome abnormality, nearly half of which are Down syndrome (Snijders, 1998).
Sagittal image of a normal, 12-week fetus demonstrating correct caliper placement (+) for nuchal translucency measurement. The fetal nasal bone and overlying skin are indicated. The nasal tip and the 3rd and 4th ventricles (asterisk), which are other landmarks that should be visible in the nasal bone image, are also shown. (Image contributed by Dr. Michael Zaretsky.)
As shown in Table 14-5, as an isolated marker, NT detects 64 to 70 percent of fetuses with Down syndrome at a false-positive rate of 5 percent, and it has maximal sensitivity at 11 weeks (Malone, 2005b). The risk conferred by an increased NT thickness is independent of that of serum analytes, and combining NT with serum analyte values results in greatly improved aneuploidy detection (Spencer, 1999). Thus, NT is generally used as an isolated marker only in screening for multifetal gestations, in which serum screening is not as accurate or may not be available (American College of Obstetricians and Gynecologists, 2013c). An exception is that if the NT measurement is increased to 3 to 4 mm, then the aneuploidy risk is unlikely to be normalized using serum analyte assessment, and invasive testing should be offered (Comstock, 2006).
Increased NT thickness is also associated with other aneuploidies, genetic syndromes, and various birth defects, especially fetal cardiac anomalies (Atzei, 2005; Simpson, 2007). Because of this, if the NT measurement is 3.5 mm or greater, the patient should be offered targeted sonography, with or without fetal echocardiography, in addition to fetal karyotyping (American College of Obstetricians and Gynecologists, 2013c).
The NT must be imaged and measured with a high degree of precision for aneuploidy detection to be accurate. This has led to standardized training, certification, and ongoing quality review programs. In the United States, training, credentialing, and monitoring are available through the Nuchal Translucency Quality Review (NTQR) program (www.ntqr.org). Training is also available through the Fetal Medicine Foundation (www.fetalmedicineusa.com). In addition to nuchal translucency, NTQR provides an educational process leading to certification in measurement of the fetal nasal bone, which is discussed on Pregnancies at Increased Risk for Genetic Disorders and shown in Figure 14-5.
Two analytes used for first-trimester aneuploidy screening are human chorionic gonadotropin—either intact or free β-hCG—and pregnancy-associated plasma protein A (PAPP-A). In cases of fetal Down syndrome, the first-trimester serum free β-hCG level is higher, approximately 2.0 MoM, and the PAPP-A level is lower, approximately 0.5 MoM. With trisomy 18 and trisomy 13, levels of both analytes are lower (Cuckle, 2000; Malone, 2005b; Spencer, 1999, 2000; Tul, 1999). If gestational age is correct, the use of these serum markers—without NT measurement—results in detection rates for fetal Down syndrome up to 67 percent at a false-positive rate of 5 percent (Wapner, 2003). Aneuploidy detection is significantly greater if these first-trimester analytes are either: (1) combined with the sonographic NT measurement or (2) combined with second-trimester analytes, which is termed serum integrated screening (Combined First-Trimester Screening).
In twin pregnancies, serum free β-hCG and PAPP-A levels are approximately doubled compared with singleton values (Vink, 2012). Even with specific curves, a normal dichorionic cotwin will tend to normalize screening results, and thus, the aneuploidy detection rate is at least 15-percent lower (Bush, 2005).
Combined First-Trimester Screening
The most commonly used screening protocol combines the NT measurement with serum hCG and PAPP-A. Using this protocol, Down syndrome detection rates in large prospective trials range from 79 to 87 percent, at a false-positive rate of 5 percent (see Table 14-5). The detection rate is approximately 5-percent higher if performed at 11 compared with 13 weeks (Malone, 2005b). The detection rate for trisomies 18 and 13 is approximately 90 percent, at a 2-percent false-positive rate (Nicolaides, 2004; Wapner, 2003).
Maternal age does affect the performance of first-trimester aneuploidy screening tests. In prospective trials, combined first-trimester screening resulted in Down syndrome detection rates of 67 to 75 percent in women younger than 35 years at delivery, which are 10-percent lower than the overall detection rates in these studies (Malone, 2005b; Wapner, 2003). Among women older than 35 at delivery, however, Down syndrome detection rates were 90 to 95 percent, albeit at a higher false-positive rate of 15 to 22 percent.
Unexplained Abnormalities of First-Trimester Analytes
There is a significant association between serum PAPP-A levels below the 5th percentile and preterm birth, growth restriction, preeclampsia, and fetal demise (Dugoff, 2004). Similarly, low levels of free β-hCG have been associated with fetal demise (Goetzl, 2004). The sensitivity and positive-predictive values of these markers are considered too low to be clinically useful as screening tests. As with other serum analyte level abnormalities, no management strategies have been demonstrated to improve pregnancy outcomes when these marker levels are abnormally low (Dugoff, 2010).
Pregnancies with fetal Down syndrome are characterized by lower maternal serum AFP levels—approximately 0.7 MoM, higher hCG levels—approximately 2.0 MoM, and lower unconjugated estriol levels—approximately 0.8 MoM (Merkatz, 1984; Wald, 1988). This triple test can detect 61 to 70 percent of Down syndrome cases as shown in Table 14-5 (Alldred, 2012). Levels of all three markers are decreased in the setting of trisomy 18, with a detection rate similar to that for Down syndrome at a false-positive rate of only 0.5 percent (Benn, 1999).
Levels of a fourth marker—dimeric inhibin alpha—are elevated in Down syndrome, with an average value of 1.8 MoM (Spencer, 1996). The addition of dimeric inhibin to the other three markers is the quadruple or quad test, which has a trisomy 21 detection rate of approximately 80 percent at a false-positive rate of 5 percent (see Table 14-5). As with first-trimester screening, aneuploidy detection rates will be slightly lower in younger women and higher in women older than 35 years at delivery. If second-trimester serum screening is used in twin pregnancies, aneuploidy detection rates are significantly lower (Vink, 2012).
The quad test is the most commonly used second-trimester serum screening test for aneuploidy. As a stand-alone test, it is generally used if women do not begin care until the second-trimester or if first-trimester screening is not available. As subsequently discussed, combining the quad test with first-trimester screening yields even greater aneuploidy detection rates.
Unexplained Abnormalities of Second-Trimester Analytes
There is a significant association between second-trimester elevation of either hCG or dimeric inhibin alpha levels and adverse pregnancy outcomes. The outcomes reported are similar to those associated with AFP level elevation and include fetal-growth restriction, preeclampsia, preterm birth, fetal demise, and stillbirth. Moreover, the likelihood of adverse outcome is increased when multiple marker levels are elevated (Dugoff, 2005). However, the sensitivity and positive predictive values of these markers are considered too low to be useful for screening or management (Dugoff, 2010).
Low Maternal Serum Estriol Levels
A maternal serum estriol level < 0.25 MoM has been associated with two uncommon but important conditions. The first, Smith-Lemli-Opitz syndrome, is an autosomal recessive condition characterized by mutations in the 7-dehydrocholesterol reductase gene. It may be associated with central nervous system, heart, kidney, and extremity abnormalities, with ambiguous genitalia, and with fetal-growth restriction. For this reason, the Society for Maternal-Fetal Medicine has recommended that sonographic evaluation be performed if an unconjugated estriol level is < 0.25 MoM (Dugoff, 2010). If abnormalities are identified, an elevated amnionic fluid 7-dehydrocholesterol level can confirm the diagnosis.
The second condition is steroid sulfatase deficiency, also known as X-linked ichthyosis. It is typically an isolated condition, but it may also occur in the setting of a contiguous gene deletion syndrome (Chap. 13, Microdeletion Syndromes). In such cases, it may be associated with Kallmann syndrome, chondrodysplasia punctata, and/or mental retardation (Langlois, 2009). If the estriol level is < 0.25 MoM and the fetus appears to be male, fluorescence in situ hybridization to assess the steroid sulfatase locus on the X-chromosome may be considered (Dugoff, 2010).
Combined First- and Second-Trimester Screening
Combined screening strategies enhance aneuploidy detection. For this reason, the American College of Obstetricians and Gynecologists (2013c) recommends that a strategy incorporating both first- and second-trimester screening should be offered to women who seek prenatal care in the first trimester. Three types of screening strategies are available:
Integrated screening combines results of first- and second-trimester tests. This includes a combined measurement of fetal NT and serum analyte levels at 11 to 14 weeks’ gestation plus quadruple markers at 15 to 20 weeks. An aneuploidy risk is then calculated from these seven parameters. As expected, integrated screening has the highest Down syndrome detection rate—94 to 96 percent at a false-positive rate of 5 percent (see Table 14-5). If NT measurement is not available, serum integrated screening includes all six serum markers to calculate risk. This screening, however, is less effective.
Sequential screening discloses the results of first-trimester screening to women at highest risk, who are then offered invasive testing with chorionic villus sampling or amniocentesis. There are two testing strategies in this category:
With stepwise sequential screening, women with first-trimester screen results that confer risk for Down syndrome above a particular threshold are offered invasive testing, and the remaining women receive second-trimester screening. The threshold is set at approximately 1 percent, because in a screened population, the 1 percent at highest risk includes approximately 70 percent of Down syndrome pregnancies (Cuckle, 2005). This method of screening may achieve up to a 95-percent detection rate (see Table 14-5).
With contingent sequential screening, women are divided into high-, moderate-, and low-risk groups. Those at highest risk, for example, the top 1 percent, are offered invasive testing. Women at moderate risk, who comprise 15 to 20 percent of the population, undergo second-trimester screening. The remaining 80 to 85 percent, who are at or below a 1:1000 risk, receive negative screening test results and have no further testing (Cuckle, 2005). Thus, most of those screened are provided with results almost immediately while still maintaining a high detection rate. This rate ranges from 88 to 94 percent (see Table 14-5). This option is also more cost-effective because a second-trimester test is obviated in up to 85 percent of patients.
Integrated and sequential screening strategies require coordination between the provider and laboratory to ensure that the second sample is obtained during the appropriate gestational age window, sent to the same laboratory, and linked to the first-trimester results.
Cell-Free Fetal DNA Screening
Using massively parallel sequencing or chromosome selective sequencing to isolate cell-free fetal DNA from maternal plasma, fetal Down syndrome and other autosomal trisomies may be detected as early as 10 weeks’ gestation (Chap. 13, Fetal DNA in the Maternal Circulation). Recent trials of these techniques in high-risk pregnancies have yielded detection rates for trisomies 21, 18, and 13 of approximately 98 percent at a false-positive rate of 0.5 percent or less (American College of Obstetricians and Gynecologists, 2012b; Bianchi, 2012; Palomaki, 2011, 2012; Sparks, 2012). This novel technology has recently become clinically available as a screening test, but it is not considered a replacement diagnostic test. Pretest counseling is recommended. If an abnormal result is identified, genetic counseling should be performed, and invasive prenatal diagnostic testing should be offered to confirm the results. The American College of Obstetricians and Gynecologists (2012b) currently recommends that the test may be offered to the following groups:
Women 35 years or older at delivery
Those with sonographic findings indicating increased risk for fetal aneuploidy
Those with a prior pregnancy complicated by trisomy 21, 18, or 13
Patient or partner carries a balanced robertsonian translocation indicating increased risk for fetal trisomy 21 or 13
Those with an abnormal first-, second-, or combined first- and second-trimester screening test result for aneuploidy.
The College does not recommend offering the test to women with low-risk pregnancies or multifetal gestations (American College of Obstetricians and Gynecologists, 2012b).
Major abnormalities and minor sonographic markers contribute significantly to aneuploidy detection. As shown in Table 14-6, with few exceptions, the aneuploidy risk associated with any major abnormality is high enough to warrant offering an invasive test for fetal karyotype and/or chromosomal microarray analysis (Chap. 13, Genetic Tests). Importantly, a fetus with one abnormality may have others that are less likely to be detected sonographically or even undetectable sonographically but that greatly affect the prognosis nonetheless. Most fetuses with aneuploidy that is likely to be lethal in utero—such as trisomy 18 and 13 and triploidy—usually have sonographic abnormalities that can be seen by the second trimester. However, only 25 to 30 percent of second-trimester fetuses with Down syndrome will have a major malformation that can be identified sonographically (Vintzileos, 1995).
TABLE 14-6Aneuploidy Risk Associated with Selected Major Fetal Anomalies ||Download (.pdf) TABLE 14-6 Aneuploidy Risk Associated with Selected Major Fetal Anomalies
|Abnormality ||Birth Prevalence ||Aneuploidy Risk (%) ||Common Aneuploidiesa |
|Cystic hygroma ||1/5000 ||50–70 ||45,X; 21; 18; 13; triploidy |
|Nonimmune hydrops ||1/1500–4000 ||10–20 ||21, 18, 13, 45X, triploidy |
|Ventriculomegaly ||1/1000–2000 ||5–25 ||13, 18, 21, triploidy |
|Holoprosencephaly ||1/10,000–15,000 ||30–40 ||13, 18, 22, triploidy |
|Dandy-Walker malformation ||1/12,000 ||40 ||18, 13, 21, triploidy |
|Cleft lip/palate ||1/1000 ||5–15 ||18, 13 |
|Cardiac defects ||5–8/1000 ||10–30 ||21; 18; 13; 45,X; 22q11.2 microdeletion |
|Diaphragmatic hernia ||1/3000–4000 ||5–15 ||18, 13, 21 |
|Esophageal atresia ||1/4000 ||10 ||18, 21 |
|Duodenal atresia ||1/10,000 ||30 ||21 |
|Gastroschisis ||1/2000–4000 ||No increase || |
|Omphalocele ||1/4000 ||30–50 ||18, 13, 21, triploidy |
|Clubfoot ||1/1000 ||5–30 ||18, 13 |
Second-Trimester Sonographic Markers—”Soft Signs”
For more than two decades, investigators have recognized that the sonographic detection of aneuploidy, particularly Down syndrome, may be improved by minor markers that are collectively referred to as “soft signs.” Minor markers are normal variants rather than fetal abnormalities, and in the absence of aneuploidy or an associated abnormality, they do not significantly affect prognosis. Examples of these sonographic findings are listed in Table 14-7. Six of these markers have been the focus of genetic sonogram studies, in which likelihood ratios have been derived that allow a numerical risk to be calculated (Table 14-8). They are generally used only from 15 to 20 or 22 weeks’ gestation. The aneuploidy risk increases steeply with the number of markers identified.
TABLE 14-7Second-Trimester Sonographic Markers or “Soft Signs” Associated with Down Syndrome Fetuses ||Download (.pdf) TABLE 14-7 Second-Trimester Sonographic Markers or “Soft Signs” Associated with Down Syndrome Fetuses
|Sonographic Markera |
Brachycephaly or shortened frontal lobe
Clinodactyly (hypoplasia of the 5th digit middle phalanx)
Echogenic intracardiac focus
Nasal bone absence or hypoplasia
Nuchal fold thickening
Renal pelvis dilation (mild)
“Sandal gap” between first and second toes
Shortened ear length
Single transverse palmar crease
Single umbilical artery
Widened iliac angle
TABLE 14-8Likelihood Ratios and False-Positive Rates for Isolated Second-Trimester Markers Used in Down Syndrome Screening Protocols ||Download (.pdf) TABLE 14-8 Likelihood Ratios and False-Positive Rates for Isolated Second-Trimester Markers Used in Down Syndrome Screening Protocols
|Sonographic Marker ||Likelihood Ratio ||Prevalence in Unaffected Fetuses (%) |
|Nuchal skinfold thickening ||11–17 ||0.5 |
|Renal pelvis dilation ||1.5–1.9 ||2.0–2.2 |
|Echogenic intracardiac focus ||1.4–2.8 ||3.8–3.9a |
|Echogenic bowel ||6.1–6.7 ||0.5–0.7 |
|Short femur ||1.2–2.7 ||3.7–3.9 |
|Short humerus ||5.1–7.5 ||0.4 |
|Any one marker ||1.9–2.0 ||10.0–11.3 |
|Two markers ||6.2–9.7 ||1.6–2.0 |
|Three or more ||80–115 ||0.1–0.3 |
Unfortunately, at least 10 percent of unaffected pregnancies will have one of these soft signs, significantly limiting their utility for general population screening (Bromley, 2002; Nyberg, 2003). The incorporation of minor markers into second-trimester screening protocols has been studied primarily in high-risk populations. In this setting, detection rates of 50 to 75 percent for Down syndrome have been reported (American College of Obstetricians and Gynecologists, 2013c). With the exception of increased nuchal skinfold thickness, the identification of an isolated second-trimester marker in an otherwise low-risk pregnancy is not generally considered sufficient to warrant “high-risk” status. A metaanalysis concluded that if minor markers were used as a basis to decide whether to offer amniocentesis, more fetal losses would result than cases of Down syndrome identified (Smith-Bindman, 2001). The American College of Obstetricians and Gynecologists (2013c) recommends that risk adjustment based on second-trimester sonographic markers be limited to specialized centers.
The nuchal skinfold is measured in the transcerebellar view of the fetal head, from the outer edge of the skull to the outer border of the skin (Fig. 14-6A). A measurement ≥ 6 mm is typically considered abnormal (Benacerraf, 1985). This finding is present in approximately 1 per 200 pregnancies and confers a more than tenfold risk for Down syndrome (Bromley, 2002; Nyberg, 2001; Smith-Bindman, 2001). Unlike the other markers listed in Table 14-8, nuchal skinfold thickening should prompt targeted sonography and consideration of amniocentesis even as an isolated finding in an otherwise low-risk patient.
Minor sonographic markers that are associated with increased risk for fetal Down syndrome. A. Nuchal skinfold thickening (bracket). B. Echogenic intracardiac focus (arrow). C. Mild renal pelvis dilatation (pyelectasis) (arrows). D. Echogenic bowel (arrow). E. Clinodactyly—hypoplasia of the 5th finger middle phalanx creates an inward curvature (arrow). F. “Sandal-gap.”
An echogenic intracardiac focus (EIF) is a focal papillary muscle calcification that is neither a structural nor functional cardiac abnormality. It is usually left-sided (Fig. 14-6B). An EIF is present in approximately 4 percent of fetuses, but it may be found in up to 30 percent of Asian individuals (Shipp, 2000). As an isolated finding, an EIF approximately doubles the risk for fetal Down syndrome (see Table 14-8). Particularly if bilateral, they are also common with trisomy 13 (Nyberg, 2001).
As discussed in Chapter 10 (Kidneys and Urinary Tract), mild renal pelvis dilatation is usually transient or physiological and does not represent an underlying abnormality (Nguyen, 2010). The renal pelves are measured in a transverse image of the kidneys, anterior-to-posterior, with calipers placed at the inner borders of the fluid collection (Fig. 14-6C). A measurement 4 mm or greater is found in about 2 percent of fetuses and approximately doubles the risk for Down syndrome (see Table 14-8). The degree of pelvic dilatation beyond 4 mm correlates with the likelihood of an underlying renal abnormality, and additional evaluation is generally performed at approximately 34 weeks (Chap. 10, Duplicated Renal Collecting System).
Echogenic fetal bowel appears as bright as bone and is seen in approximately 0.5 percent of pregnancies (Fig. 14-6D). Although typically associated with normal outcomes, it increases the risk for Down syndrome approximately sixfold (see Table 14-8). Echogenic bowel may represent small amounts of swallowed blood and may be seen in the setting of AFP level elevation (Management of the Fetus with Spina Bifida). It has also been associated with fetal cytomegalovirus infection and cystic fibrosis—representing inspissated meconium in the latter.
The femur and humerus are slightly shorter in Down syndrome fetuses, although the femur length to abdominal circumference (FL/AC) ratio is generally within the normal range in the second trimester. The femur is considered “short” for Down syndrome screening if it measures ≤ 90 percent of that expected. The expected femur length is that which correlates with the measured biparietal diameter (Benacerraf, 1987). Although this finding may be identified in approximately 4 percent of fetuses, its sensitivity may vary with ethnicity. As an isolated finding in an otherwise low-risk pregnancy, it is generally not considered to pose great enough risk to warrant counseling modification. Similarly, a humerus shortened to ≤ 89 percent of expected, based on a given biparietal diameter, has also been associated with an increased risk for Down syndrome (see Table 14-8).
First-Trimester Sonographic Findings
Unlike second-trimester soft signs, which may be readily visible during a standard sonogram, first-trimester findings associated with aneuploidy require specialized training. The fetal NT is unique in that it has become a component of aneuploidy screening offered to all women. Other first-trimester findings associated with an increased risk for fetal Down syndrome include an absent fetal nasal bone, wider frontomaxillary facial angle—indicating a flat facial profile, tricuspid regurgitation, and abnormal ductus venosus flow (Borenstein, 2008; Cicero, 2001; Faiola, 2005; Huggon, 2003; Matias, 1998; Sonek, 2007). Each has also been associated with an increased risk for trisomies 18 and 13 and other aneuploidies. However, these signs have not become widely adopted for routine use in the United States.
In approximately two thirds of fetuses with Down syndrome, the nasal bone is not visible at the 11- to 14-week examination (Cicero, 2004; Rosen, 2007; Sonek, 2006). Currently, this is the only first-trimester marker, other than NT, for which the Nuchal Translucency Quality Review Program has established a training program. Criteria for adequate assessment include that the fetus occupies most of the image; that there be a 45-degree angle of insonation with the fetal profile; that the profile be well defined in the midsagittal plane, with the tip of the nose and the third and fourth ventricles visible; and that the nasal bone brightness be greater than or equal to that of the overlying skin (Nuchal Translucency Quality Review Program, 2013). An example is shown in Figure 14-5. Initial optimism for this marker was somewhat dampened when the FASTER (First- and Second-Trimester Evaluation of Risk) trial concluded that difficulty in performing the assessment would limit its usefulness for aneuploidy screening (Malone, 2004, 2005a).