Sonographic Markersof Fetal TrisomiesSecond Trimester

David A. Nyberg, MD, Vivienne L. Souter, MD, MRCOG

Objective. Second-trimester sonographic findings of fetal trisomy may include structural abnormali-ties or sonographic markers of fetal aneuploidy. Unlike structural anomalies, sonographic markers offetal aneuploidy are insignificant by themselves with regard to outcome, are nonspecific—most fre-quently seen in normal fetuses, and are often transient. Our objective was to review the second-trimester sonographic findings of the major trisomic conditions, trisomies 13, 18, and 21. Methods.We reviewed a number of the most commonly accepted markers, including nuchal thickening, hyper-echoic bowel, echogenic intracardiac focus, renal pyelectasis, shortened extremities, mild cerebral ven-tricular dilatation, and choroid plexus cysts. Markers associated with trisomy 21 were emphasized.Results. The sensitivity of sonography for detection of fetal trisomic conditions varies with the type ofchromosome abnormality, gestational age at the time of sonography, reasons for referral, criteria forpositive sonographic findings, and the quality of the sonography. As an estimate, 1 or more sono-graphic findings can be identified in approximately 90% of fetuses with trisomy 13, 80% of fetuseswith trisomy 18, and 50% to 70% of fetuses with trisomy 21 (Down syndrome). Conclusions. Thepresence or absence of sonographic markers can substantially modify the risk of fetal Down syndromeand is the basis of the so-called genetic sonogram. Because maternal biochemical and sonographicmarkers are largely independent, combined risk estimates will result in even higher detection ratesthan either alone. Key words: trisomy 21; trisomy 18; trisomy 13; Down syndrome; prenatal sonog-raphy; nuchal thickening; hyperechoic bowel; echogenic intracardiac foci; pyelectasis; choroid plexuscyst; ventricular dilatation.

Received February 14, 2001, from the Center forPerinatal Studies, Seattle Medical Center (D.A.N.),and Departments of Radiology (D.A.N.), Obstetricsand Gynecology (D.A.N.), and Genetics (V.L.S.),University of Washington Medical Center, Seattle,Washington. Revision requested February 20, 2001.Revised manuscript accepted for publicationFebruary 20, 2001.

Address correspondence to David A Nyberg,MD, 1229 Madison St, 1150, Seattle, WA 98104.

AbbreviationsAAURA, age-adjusted ultrasound risk assessment; EIF,echogenic intracardiac foci; hCG, human chorionicgonadotropin; IUGR, intrauterine growth restriction;SMFA, sonographic markers of fetal aneuploidy

onography can show abnormalities in many fetus-es with chromosomal aberrations.1,2 These mayinclude both major or structural defects and non-structural findings, also known as sonographic

markers. Unlike structural anomalies, sonographic mark-ers of fetal aneuploidy (SMFA) are insignificant by them-selves with regard to outcome, are nonspecific—mostfrequently seen in normal fetuses, and are often tran-sient. The most common SMFA in the second trimesterare nuchal thickening, hyperechoic bowel, shortenedextremities, renal pyelectasis, echogenic intracardiac foci(EIF), and choroid plexus cysts.

Table 1 summarizes the common structural anomaliesand sonographic markers associated with the 3 commontrisomic conditions (trisomies 13, 18, and 21). Althougheach trisomic condition has a typical phenotype, there iswide variation in phenotypic expression. The sensitivity ofsonography for detecting these abnormalities varies witha number of factors, including the type of chromosomeabnormality, gestational age at the time of sonography,

© 2001 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 20:655–674, 2001 • 0278-4297/01/$3.50

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reasons for referral, criteria for positive sonograph-ic findings, and the quality of the sonography.

As an estimate, major or structural abnormali-ties are seen in 20% of fetuses with trisomy 21(Down syndrome) during the second trimester,whereas they are seen in most fetuses with tri-somies 18 and 13.3–7 Combined with SMFA,sonographic findings are identified in approxi-mately 50% to 70% of fetuses with Down syn-drome, 80% of fetuses with trisomy 18, and 90%of fetuses with trisomy 13. This emphasizes thepotential importance of nonstructural markersin detection of fetal trisomy.

In the following sections, we review the second-trimester sonographic findings of themajor trisomic conditions, trisomies 13, 18,and 21. We emphasize fetal Down syndromebecause it is the most common trisomic con-dition, the most likely to result in a survivingneonate, and the most likely to show SMFAwithout structural anomalies.

Trisomy 13

In trisomy 13, malformations of the central ner-vous system are common. These may includeholoprosencephaly, agenesis of the corpus callo-sum, Dandy-Walker malformation, vermianagenesis, and neural tube defects. Other com-

mon malformations detected are facial abnor-malities, including cyclopia, hypotelorism, andcleft lip and palate (Fig. 1A), renal cystic dysplasiaor hydronephrosis, cardiovascular malforma-tions, cystic hygroma, polydactyly, and club orrocker-bottom feet.

MarkersNonspecific markers of trisomy 13 may includemild dilatation of the lateral cerebral ventricles,hyperechoic bowel, and EIF. Lehman et al6 report-ed EIF in 39% of fetuses with trisomy 13 before 20weeks. Multiple EIF probably increase the risk ofaneuploidy, including trisomy 13 (Fig. 1B). Thecombination of EIF and a hypoplastic-appearingleft side of the heart is a characteristic pattern oftrisomy 13 (Fig. 2).6 We have encountered 1 caseof trisomy 13 in which multiple EIF was the onlysonographic finding and several other cases inwhich EIF was the initial finding that led todetection of other subtle anomalies. Because ofits association with trisomy 21, EIF is discussedfurther below (see “Trisomy 21”).

Trisomy 18

A wide diversity of sonographic and pathologicabnormalities have been associated with trisomy18 during the second trimester, including cystic

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Table 1. Common Structural Anomalies and Sonographic Markers Associated With the 3 Common Trisomic Conditions

Trisomy 21 Trisomy 18 Trisomy 13

Major anomalies Cardiac defects Cardiac defects Cardiac defects Duodenal atresia Spina bifida Central nervous system abnormalitiesCystic hygroma Cerebellar dysgenesis Facial anomalies

Micrognathia Cleft lip/palateOmphalocele Urogenital anomaliesClenched hands/wrists Echogenic kidneysRadial aplasia OmphaloceleClub feet PolydactylyCystic hygroma Rocker-bottom feet

Cystic hygromaMarkers Nuchal thickening* Choroid plexus cysts* EIF*

Hyperechoic bowel* Brachycephaly IUGREIF* Shortened limbs PyelectasisShortened limbs* IUGR Single umbilical arteryPyelectasis* Single umbilical arteryMild ventriculomegaly*ClinodactylySandal gapWidened pelvic anglePericardial effusionRight-left heart disproportion

*Discussed in greater detail in text.

hygroma, nonimmune hydrops, hydrocephalus,spina bifida, diaphragmatic hernia, tracheo-esophageal fistula, genitourinary anomalies,cardiovascular malformations, and omphalo-cele. Subtle abnormalities may include ver-mian agenesis and8,9 small-bowel–containingomphalocele (Fig. 3),10,11 Skeletal abnormalitiesare common and include clenched hands (Fig.4),12,13 club feet, and radial aplasia or limb short-ening. In the third trimester, some fetuses withtrisomy 18 may primarily have intrauterinegrowth restriction (IUGR), which is often associ-ated with polyhydramnios.

MarkersSubtle or nonstructural findings of trisomy 18may include choroid plexus cysts, brachy-cephaly or “strawberry-shaped” head,14 and sin-gle umbilical artery.15 Of these, choroid plexuscysts (Fig. 5) have been the most controversialand the subject of considerable interest.16–21 Likeother SMFA, choroid plexus cysts are a relativelycommon variant during the second trimester,are transient, and have no known effect on fetal

development. Unlike some of the other potentialmarkers (e.g., nuchal thickening and hyper-echoic bowel), choroid plexus cysts have noknown association with other adverse outcomeswhen the karyotype is normal.

Variables that may influence detection ofchoroid plexus cysts include gestational age, thethoroughness of the sonography, the thresholdfor calling a finding a choroid plexus cyst, under-lying risk factors, and reasons for referral. Itshould be noted that studies that restrictpatients to those with known karyotypes may bebiased, because sonographic findings influencepatients’ decisions about invasive testing. High-risk patients with SMFA are more likely to under-go invasive testing than low-risk patients withthe same findings. For this reason, a higher riskwill be found among patients who choose inva-sive testing compared with patients who do not.Snijders et al22 reported that among 107 fetuseswith isolated choroid plexus cysts who had kary-otyping, 2 had chromosome defects (1 each oftrisomy 18 and 21), whereas no chromosomeabnormality was found among the 174 fetuses

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Figure 1. Trisomy 13. A, Bilateral cleft lip and plate. Coronal view of the face shows features of bilateral cleft lip and palate, seen as premaxillary pro-trusion (arrows). O indicates orbits. B, Bilateral EIF. Transverse view of the heart with the apex away from the transducer shows prominent bilateral EIF(arrows). No other abnormalities were identified in this fetus. LV indicates left ventricle; RV, right ventricle; and Sp, spine.

A B

with choroid plexus cysts who did not haveamniocentesis. Similar results can be found withother SMFA.

The prevalence of choroid plexus cysts in thegeneral population has been reported as 0.5% to3.6%, with most studies reporting in the range of1% to 2%.23,24 At our own center, which has high-risk patients, we observe choroid plexus cysts inapproximately 3.5% of fetuses at 14 to 20 weeks.In comparison, choroid plexus cysts areobserved in 30% to 40% of fetuses with trisomy18 before 20 weeks. This might suggest a high riskfor trisomy 18 when choroid plexus cysts areidentified prenatally. However, because mostfetuses with trisomy 18 have other abnormalities,the risk from isolated choroid plexus cysts is rela-tively low.

Snijders et al22 observed choroid plexus cysts in50% of fetuses with trisomy 18 and 1% of karyo-typically normal fetuses. They found that isolatedchoroid plexus cysts carried only a marginallyincreased risk (likelihood ratio <2) for trisomy18, but the presence of another abnormalityincreased the risk approximately 20 times(Table 2). The authors suggested that maternalage should be the main factor in decidingwhether to offer fetal karyotyping when isolatedchoroid plexus cysts are detected. Similar opin-ions have been reached by a number of otherauthorities, including Chitty et al,25 who evalu-ated 658 fetuses with choroid plexus cysts.

Two meta-analyses found higher likelihoodratios for isolated choroid plexus cysts and tri-somy 18 compared with that of Snijders et al.22

Ghidini and colleagues26 observed that isolatedchoroid plexus cysts were detected in 6.7% (13 of194) of fetuses with trisomy 18 and 0.9% (752 of79,583) of control fetuses, yielding a likelihoodratio of 7.1. In another report, Yoder et al27 evalu-ated 13 prospective studies comprising 246,545second-trimester scans and found a likelihoodratio of 13.8 for trisomy 18. Despite this relativelyhigh likelihood ratio, the authors concluded thatfetal karyotyping should be offered only whenmaternal age at delivery is 36 years or older orwhen the risk for trisomy 18 detected by serummultiple-marker screening is more than 1 per3000.

Among other variables, there is good evidenceto suggest that larger choroid plexus cysts furtherincrease the risk of trisomy 18 compared withsmaller cysts (Fig. 6).28–32 Such large cystsundoubtedly take longer to resolve, supporting

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Sonographic Markers of Fetal Trisomies: Second Trimester

Figure 2. Trisomy 13 and EIF. Four-chamber view of the heart shows EIF (arrow) inthe left ventricle and the disproportionately smaller size of the left ventricle and leftatrium compared with the right-sided chambers. A ventricular septal defect is alsopresent. Other anomalies included single umbilical artery and probable cleft lip andpalate. LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, rightventricle.

Figure 3. Trisomy 18 and omphalocele. Transverse view of the abdomen at 17weeks shows small-bowel–containing omphalocele (arrows). A strawberry-shapedhead was also present. Sp indicates spine.

observations that delayed resolution of choroidplexus cysts carries an increased risk for trisomy18. Whether the cysts are unilateral or bilateraldoes not appear to be significant, although it isprobably true that large cysts also tend to bebilateral.

All of these findings indicate that detection of achoroid plexus cyst, as with any SMFA, shouldinitiate a renewed search for other abnormalities.A choroid plexus cyst can be presumed to be iso-lated only after a detailed fetal survey fails toshow structural abnormalities or other SMFA. Asan isolated finding after high-quality sonogra-phy, and assuming the patient is otherwise con-sidered at low risk for fetal aneuploidy, we thinkthat detection of choroid plexus cysts should notalter obstetric management. Additional reassur-ance can be obtained by correlating sonographicfindings with serum biochemical markers.33,34

Because choroid plexus cysts always resolve, follow-up sonography is of no value in decisionmaking unless it is done to detect other abnormal-ities that were previously missed (e.g., cardiacdefects).

Trisomy 21

Structural or major abnormalities in trisomy 21include cardiac defects, hydrops, and cystichygroma. Rarely, duodenal atresia can also beseen before 20 weeks, especially when com-bined with esophageal atresia.35–37

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Figure 6. Trisomy 18 and large choroid plexus cyst. A large choroid plexus cyst (C)measuring 16 mm in length is shown in the dependent ventricle. No other sono-graphic abnormalities were identified in this case.

Figure 4. Trisomy 18 and clenched hand. A typical clenched hand (H)is shown.

Figure 5. Trisomy 18 and choroid plexus cyst. Image of the head at 18 weeks shows a typical choroid plexus cyst (arrow) measuring 5 mm.Other abnormalities in this case included a diaphragmatic hernia, a car-diac defect, and probably micrognathia.

Table 2. Approximate Risk of Trisomy 18 in FetusesWith Choroid Plexus Cysts

Gestational Baseline Isolated OtherAge, wk Risk Cyst Abnormalities

20–24 1:4500 1:2950 1:22525–29 1:3600 1:2300 1:17530–34 1:2000 1:1300 1:10035–39 1:750 1:470 1:3540–44 1:400 1:100 1:10

Data from Snijders et al.22

Compared with fetuses with trisomies 18 and13, fetuses with trisomy 21 are unlikely to havestructural abnormalities before 20 weeks. Sohl etal38 found major abnormalities in 16.4% of fetus-es with trisomy 21, and we found major abnor-malities in 16.7% before 20 weeks, after exclusionof patients referred for sonographically detectedabnormalities.39 A slightly higher frequency(21.8%) of structural abnormalities was found ina previous study at our center, but that studyincluded referred patients and also categorizedmild ventricular dilatation as a major abnormal-ity for consistency with previous studies.40,41

Studies that include patients referred for sono-graphically detected abnormalities will have ahigher rate of major abnormalities.

The low detection rate of structural abnormali-ties reflects the low sensitivity of sonography fordetection of cardiac defects among fetuses withtrisomy 21 before 20 weeks. We consistentlydetect cardiac defects in less than 10% of fetuseswith trisomy 21, although the mean gestationalage at the time of scanning is 16.9 weeks for thesepregnancies. Improved detection of cardiacdefects would be expected even a few weekslater. Using nonspecific cardiac findings, such asright-left disproportion, pericardial effusion, andtricuspid regurgitation, DeVore et al42 reportedcardiac findings in 76% of fetuses with trisomy21, but just 9% had an endocardial cushiondefect. The mean gestational age for sonographyin that study was also 18 weeks.

A study by Paladini and colleagues43 suggestedwhat is possible under ideal conditions. Scanningat an optimal gestational age (24 weeks), underoptimal conditions (in a dedicated fetal echo-cardiographic center), with inclusion of subtleventricular septal defects, and with previousknowledge of fetal karyotype, they were able todetect heart defects in just more than half offetuses with Down syndrome.

MarkersA large number of potential SMFA have beendescribed in association with trisomy 21 duringthe second trimester (Table 1).40,41,44–47 Amongthese, we routinely evaluate nuchal thickening,hyperechoic bowel, EIF, shortened limbs, andpyelectasis, because they can be easily soughtduring the course of routine second-trimestersonography. Other potential markers include awidened pelvic angle,48–51 shortened frontallobes,52,53 small ears,54 clinodactyly,55 pericardial

effusion, and right-left disproportion of theheart, among others. Another potential markerfor trisomy 21, although not related to fetalanatomy, is unfused amnion and chorion after 14weeks.56

The sensitivities of most sonographic markersare low, particularly compared with that ofnuchal translucency in the first trimester (Table 3).However, the incremental value of each markerimproves the overall sensitivity of second-trimester sonography so that 1 or more markersare observed in more than 50% of fetuses withtrisomy 21 at our center. When SMFA are com-bined with major abnormalities, our overall sen-sitivity of second-trimester sonography is 69%.

The use of sonographic markers, usually apanel of markers, to modify the risk of fetal Downsyndrome is widely referred to as a “genetic sono-gram.” The actual sensitivity of a genetic sono-gram will depend on various factors, includingthe markers sought, gestational age, reasons forreferral,56A and, of course, the quality of thesonography. Considering these variables and dif-ferences in the types of sonographic markersused (Table 4), the results for genetic sonogramsfrom different centers are surprisingly similar(Table 5). Reported detection rates have rangedfrom 59% to 82%. Detection rates exceeding 90%have even been reported, including a high detec-tion rate for cardiac abnormalities.42

The risk of fetal trisomy 21 increases dramati-cally with the number of markers present (Table6). Two or more markers are detected in nearlyone third of fetuses with trisomy 21 at our center,compared with less than 2% in normal fetuses. Incomparison, a single marker is observed in morethan 11% of normal fetuses compared with22.6% of fetuses with trisomy 21. Similarly, Sohlet al38 observed a single marker in 14.6% of nor-mal fetuses. On the basis of these data, a single

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Table 3. Frequency of Sonographic Markers(Without Structural or Major Abnormalities) inFetuses With Trisomy 21

Sonographic Marker Trisomy 21 (n = 186), %

Nuchal thickening 32.3Hyperechoic bowel 17.2Short humerus 18.3Short femur 26.3EIF 23.1Pyelectasis 11.3

Data from Swedish Medical Center (Seattle, WA).

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marker increases the risk 2-fold; 2 markersincrease the risk nearly 10-fold; and 3 or moremarkers increase the risk more than 100-fold.The actual risk will depend on the type as well asthe number of markers present.

The use of multiple sonographic markers willimprove the sensitivity of sonography for detec-tion of fetal Down syndrome but at the cost of ahigher false-positive rate if the presence of any sin-gle marker is considered a positive finding. Thishigh false-positive rate can understandably lead toconsiderable anxiety57 and inconsistent manage-ment58 among low-risk patients. Sonologistsshould attempt to minimize these false-positiveresults among low-risk patients but should maxi-mize the sensitivity in high-risk patients.

To optimize clinical management of sono-graphic markers, Benacerraf and colleagues40,41

devised a scoring index in which 2 points aregiven for structural abnormalities or nuchalthickening and 1 point is given for the othermarkers. Amniocentesis is offered to those witha score of 2 or greater. This approach avoids thefalse-positive rates from a single marker, exceptfor nuchal thickening, which is appropriately

considered a high-risk marker. The scoringindex system can be modified to incorporatematernal age by giving 1 point for women 35years of age or older and 2 points for women 40years of age or older (Table 7).59 With this modi-fication, a single sonographic marker would beconsidered a positive result for higher-riskwomen 35 to 39 years of age, and advancedmaternal age alone would be sufficient criteriafor women 40 years of age or older. A primaryadvantage of the scoring index method is that itis easy to use and understand.

Another method of optimizing sonographicfindings is to integrate the risk of sonographicmarkers with the a priori risk based on maternalage. This has been termed “age-adjusted ultra-sound risk assessment” (AAURA) for Down syn-drome.45 The sonographic markers are weightedby the strength of individual findings, expressedas likelihood ratios (Table 7). The post priori riskis estimated by the likelihood ratios, and the apriori risk is based on maternal age (Table 8).

When AAURA is used, both the sensitivity offetal Down syndrome and the false-positive rateincrease with maternal age. This is appropriate

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Table 4. Components of the Second-Trimester Genetic Sonogram Reported in Various Studies for Detectionof Fetal Down Syndrome

Report Nuchal Humerus Femur Renal HB EIF CC Other

Benacerraf et al41 + + + + + – + –DeVore134 + – – + + + + +Nyberg et al45 + + + + + + – –Bahado-Singh et al71 + + – – + – + –Vergani et al47 + – – – – – – –Sohl et al38 + – – – + + + +Vintzileos56A + + + + + + + +++

CC indicates choroid plexus cysts; HB, hyperechoic bowel; and +++, multiple other findings.

Table 5. Sensitivities and False-Positive Rates Reported for Genetic Sonograms From Different Centers

Report n Sensitivity, % FP rate, % LR LR Negative

Benacerraf et al41 45 73 4.4 16.5 0.28DeVore134 15 73 7.4 9.9 0.29Bromley et al59 53 75 5.7 13.1 0.27Nyberg et al45 142 74 14.7 5 0.30Bahado-Singh et al71 24 60 4.5 13.3 0.41Bahado-Singh et al73 31 73.5 15 4.9 0.31Vergani et al47 22 59 5.3 11.1 0.43Sohl et al38 55 67 19.4 3.5 0.41Vintzileos56A 34 82 9 9.1 0.20Nyberg et al39 186 69.9 13.3 5.3 0.36

FP indicates false-positive; and LR, likelihood ratio. LR = sensitivity/FP rate; and LR negative = false negative rate/speci-ficity = (1 – sensitivity)/(1 – FP rate).

because older women desire high sensitivity, andthe clinical alternative is amniocentesis for allwomen 35 years of age or older (100% false-pos-itive rate). At the same time, AAURA minimizesthe false-positive rate for younger women (4%false-positive rate) but still has satisfactory sen-sitivity (61.5%). Very similar results can beobtained with the modified scoring indexmethod, which incorporates maternal age,although AAURA has the advantage of providinga patient-specific risk estimate.60 Because sono-graphic findings appear to be largely indepen-dent of both maternal age and biochemicalanalytes,61–63 we think that the risk from bio-chemical screening (serum markers plus mater-nal age risk) can be substituted for maternal agerisk alone when known.

AAURA, or any method of risk assessment,requires knowledge of the risks associated withindividual sonographic markers. In the follow-ing sections, individual markers are discussedin greater detail.

Nuchal Thickening

Redundant skin at the back of the neck is acharacteristic clinical feature of infants withtrisomy 21 and was first reported by Down in1866.64 Benacerraf and coworkers65–67 firstreported the sonographic correlate of this clin-ical feature in terms of nuchal thickening dur-ing the second trimester (Fig. 7), and thusbegan the search for other sonographic mark-ers. Nuchal thickening remains one of themost sensitive and important markers of tri-somy 21 during the second trimester. Indeed,although other criteria vary among centers,nuchal thickening is universally used as amarker for trisomy 21. Although the sensitivityand false-positive rates will vary with gesta-tional age and the exact criteria for a positivefinding, sensitivities in the range of 20% to 40%are most common.

On the basis of early experience, Benacerraf etal65 suggested that a threshold of 6 mm orgreater after 15 weeks indicated a high risk oftrisomy 21. However, in a subsequent studythey observed that none of 303 normal fetusesshowed nuchal thickening of greater than 5mm up to 20 weeks.66 Several prospective stud-ies have since suggested that 5 mm is a betterthreshold, which results in improved sensitivityand only a slight increase in the false-positiverate. We have used a 5-mm cutoff for the last 10years.68–70

A number of studies have shown that normalnuchal thickness varies with gestational age,which should not be surprising. This suggeststhat, as a further refinement, gestational age-specific criteria should be used for increasednuchal thickness rather than a single cutoff.71–73

Gestational age-specific criteria may includeobserved-to-expected or observed-minus-expected nuchal thickness or a comparison ofnuchal thickness with other biometric mea-surements, such as biparietal diameter andfemur and humerus length. The use of multi-ple-of-the-median data, comparing the actualnuchal measurement with the expected mea-surement, would permit calculation of likeli-hood ratios and would also permit integrationwith maternal serum biochemical markers fora combined risk. Bahado-Singh and coworkershave reported multiples of the median and esti-mated likelihood ratios.71–73

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Table 6. Comparison of Number of Markers in Fetuses With DownSyndrome and Controls

No. of Markers Down Controlor Major Syndrome (N = 8712),Abnormality (n = 186), % (n) % (n) LR

0 31 (58) 86.7 (7541) 0.361 22.6 (42) 11.3 (987) 2.02 15.1 (28) 1.5 (136) 9.63+ 14.5 (27) 0.1 (11) 115Major abnormality 16.7 (31) 0.4 (37) 39.2

LR indicates likelihood ratio; LR = percent Down syndrome cases/controlcases.

Table 7. Comparison of 2 Methods for Assessing the Risk of FetalDown Syndrome Based on Sonographic Findings: AAURA and theIndex Scoring System

Sonographic Finding LR (AAURA) Index Score

Structural defect 25 2Nuchal thickening 11 2Hyperechoic bowel 6.7 1Short humerus 5 1EIF 1.8 1Short femur 1.5 1Pyelectasis 1.5 1Age 35–39 y Risk based on age (Table 8) 1Age 40+ y Risk based on age (Table 8) 2If normal 0.4 0

Likelihood ratios (LR) reported are those calculated as isolated markers,from Nyberg et al.39 Slightly different likelihood ratios were assumed pre-viously in the description of AAURA.45

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Hyperechoic Bowel

Like other nonstructural markers, hyperechoicbowel is nonspecific and is most commonlyobserved in normal fetuses. However, it isobserved with increased frequency in fetuseswith aneuploidy, including trisomy 21 (Fig. 8).74–78

Hyperechoic bowel has also been reported inassociation with bowel atresia, congenital infec-tion, and, rarely, meconium ileus secondary tocystic fibrosis.79,80 An increased risk of IUGR,fetal death, and placenta-related complicationsis also recognized as being associated withhyperechoic bowel.81

Despite its subjectivity, the prevalence ofhyperechoic bowel among normal fetuses(0.5%) has been remarkably consistent at ourcenter in the last decade and is also similar tothat in other reports, suggesting that differentcenters can agree on the presence of hyper-echoic bowel. We use a grading system forhyperechoic bowel, with grade 1 being mildlyechogenic and typically diffuse, grade 2 beingmoderately echogenic and typically focal, andgrade 3 being very echogenic, similar to that ofbone structures.82 The echogenicity of normalbowel also increases with transducer frequen-

cy,83 although this effect is uniform, whereas truehyperechoic bowel tends to be focal. To mini-mize subjectivity, some authors consider onlybowel that is markedly hyperechoic, whereas weand others84,85 recognize both moderate andmarkedly hyperechoic bowel (grades 2 and 3) asa risk factor for fetal aneuploidy (Fig. 8). If onlygrade 3 hyperechoic bowel were recognized, thesensitivity would be decreased, but the risk (like-lihood ratio) would be increased.

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Table 8. A Priori Risk of Down Syndrome, Expressedas Odds Ratio, Based on Maternal Age During theSecond Trimester

Age, y Odds Ratio

20 1:117621 1:116022 1:113623 1:111424 1:108725 1:104026 1:99027 1:92828 1:85529 1:76030 1:69031 1:59732 1:50833 1:42134 1:34235 1:27436 1:21637 1:16838 1:12939 1:9840 1:7441 1:5642 1:4243 1:3144 1:23

Figure 7. Trisomy 21 and nuchal thickening. Mild nuchal thickening is shown(6 mm), delineated by calipers.

Figure 8. Trisomy 21 and hyperechoic bowel (HB). Moderately echogenic bowel isshown; it is not quite as echogenic as the adjacent bone. H indicates heart; andIW, iliac wing.

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Skeletal Abnormalities

Short stature is a characteristic feature of childrenwith trisomy 21, associated with disproportion-ately short proximal long bones (femur andhumerus). Limb shortening can also be detectedin some fetuses with trisomy 21 during the sec-ond trimester.86–91 However, there is considerableoverlap in bone measurements between affectedand unaffected fetuses. A shortened humerusappears to be a slightly more specific indicatorthan a shortened femur. Results probably varywith gestational age, ethnic group, possibly fetalgender, and criteria used, as well as systematicdifferences in long-bone measurements.92

Despite these variables, this marker is commonlyused at screening centers. The most commonmethod for determination of shortened humerusand femur is comparing the actual measurementwith the expected measurement, typically basedon biparietal diameter or another dating parame-ter rather than gestational age. Until now, we haveused a single cutoff of 0.91 multiples of the medi-an for a short femur and 0.89 for a short humerus.However, like nuchal measurements, optimalresults would be expected by multiple-of-the-median data and corresponding likelihood ratiosrather than a single cutoff.71 These methods arebest performed by computer calculations. Otherskeletal abnormalities associated with trisomy 21are clinodactyly (shortened middle phalanx of thefifth finger) and a widened pelvic angle. Althoughboth are well-known clinical features of trisomy21, these can be difficult to assess on second-trimester sonography and therefore are not typi-cally included in most screening programs.

Renal Pyelectasis

Mild pyelectasis (hydronephrosis) has been asso-ciated with an increased risk of aneuploidy,93–96

primarily for trisomy 21. However, it is mostcommonly seen as a normal variant and appearsmore commonly in male fetuses.95 The preva-lence of pyelectasis undoubtedly varies withgestational age even during the time of second-trimester scans (14–22 weeks). A mild degree ofrenal pyelectasis may fluctuate during the courseof a single examination.

Studies are conflicting regarding the possibleinfluence of pyelectasis from maternal hydrationas well as the degree of fetal bladder disten-tion.97–100 Robinson and colleagues100 found that

the anteroposterior renal pelvic diameterincreased with maternal hydration in both nor-mal fetuses and those with pyelectasis and wasindependent of the state of the fetal bladder,whereas Petrikovsky et al98 found that the degreeof fetal bladder distention was important.

Renal pyelectasis is measured as the fluid-filledrenal pelvis in an anteroposterior dimension. Weprefer measurement when the kidneys and spineare oriented toward or away from the transducerrather than to the side. The threshold for a posi-tive finding varies among centers, but the mostcommon criteria are greater than 3 to 4 mm.Ideally, gestational age-dependent criteria mightbe used in the future.

Using a cutoff of greater than 3 mm, we observepyelectasis in about 3% of normal fetuses at ourcenter. Snijders and Nicolaides101 estimate thatmild pyelectasis increases the risk of trisomy 21by 1.6-fold over the baseline risk. Our own analy-sis is consistent with this risk, although this riskmay not be increased when pyelectasis is isolat-ed. The lack of association as an isolated findinghas also been suggested by other studies,102,103

although one center has shown an association asan isolated finding.104

Echogenic Intracardiac Foci (or Papillary MuscleCalcification)

Echogenic intracardiac foci as SMFA are the mostrecent, and probably the most controversial, of thesonographic markers that have been described. Itis a common finding during the second trimester,observed in 3% to 4% of normal fetuses.105,106 Theprevalence appears to be significantly higheramong Asian populations; Shipp et al107 found EIF3 times more often among Asian patients com-pared with white patients. That finding is impor-tant, because an estimation of risk derived fromwhite populations may not apply to Asian women.

Because EIF is a subjective finding, its detectiondepends on a variety of factors, including resolu-tion of the sonographic equipment, technique,thoroughness of the examination, and the sono-grapher’s experience. Fetal position is alsoimportant, because intracardiac foci are bestvisualized when the cardiac apex is orientedtoward the transducer.108 Despite these variablefactors, similar detection rates of EIF from differ-ent studies suggest that experienced sonogra-phers can largely agree on its presence orabsence. Like many sonographic markers, it typ-

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ically resolves by the third trimester despite theoutcome.109

Roberts and Genest110 were the first to suggestan association between aneuploidy and miner-alization of the papillary muscle in a pathologicstudy. Mineralization of the papillary musclewas observed in 2% of normal fetuses comparedwith 16% (20 of 126) of those with trisomy 21 and39% (9 of 23) of those with trisomy 13. Similarbut slightly higher rates of EIF have beenobserved in sonographic studies during the second trimester, possibly because small focimay have escaped pathologic detection.Comparison of these data, as well as direct corre-lation by Brown et al,111 suggests that EIF corre-lates with papillary muscle mineralization thatcan be seen histologically.

In 2 sonographic studies of EIF and aneu-ploidy, Bromley et al112 detected EIF in 4.7% (62of 1312) of control fetuses compared with 18% (4of 22) of those with trisomy 21, and Lehman etal6 reported EIF in 39% of fetuses with trisomy 13before 20 weeks. A number of studies have con-firmed an association between EIF and trisomy21 (Fig. 9)113–118 with few exceptions.119–121 Thelikelihood ratio of EIF in trisomy 21 has beenestimated in the range of 1.8 to 4.2.

The risk of aneuploidy from isolated EIF, as wellas other SMFA, may be underestimated amonglow-risk patients because of incomplete ascer-tainment. Few patients with an isolated markerundergo chromosome analysis unless they arealready considered at high risk. In one of the fewstudies to address this issue, Simpson and col-leagues114 evaluated 205 fetuses with isolatedEIF from low-risk patients. Clinical follow-upwas obtained by way of a standard questionnairecompleted by the parents when the infants were6 weeks old. Two infants (1%) proved to haveaneuploidy (1 trisomy 21 and 1 unbalancedtranslocation).

On the other hand, the risk of EIF and othermarkers is probably overestimated in studies inwhich the fetal karyotype is known for all patients,because sonographic findings influence patientdecision making. Many high-risk patients nowwait for the results from the second-trimestersonogram before deciding to undergo geneticamniocentesis, and high-risk patients are appro-priately more likely to undergo genetic amnio-centesis than low-risk patients on the basis of thesame sonographic findings. We observed EIF in5.4% of fetuses with known normal karyotypes

compared with 3.9% of all consecutive patientswho had normal or presumed normal fetal kary-otypes. Previous studies confined to known kary-otypes have also shown a higher prevalence ofEIF. This emphasizes the potential for bias instudies of sonographic markers that restrictpatients to those with known fetal karyotypes.

Multiple or large EIF may be important vari-ables when considering genetic amniocente-sis.122–125 Bettelheim et al122 found EIF located inthe left ventricle in 96% of cases, in combined leftand right ventricles in 4.3%, and isolated to theright ventricle in just 0.7% (1 of 150). Bromley etal116 concluded that right-sided and bilateral EIFcombined together had an approximately 2-foldgreater risk of aneuploidy compared with left-sided foci, and others have also found thatechogenic foci involving both ventricles are moreassociated with aneuploidy. Wax and Philput123

reported that aneuploidy was more commonwhen echogenic foci involved both ventriclescompared with either ventricle alone. Vibhakaret al117 found that of 15 fetuses with multiple EIF,10 (67%) had abnormal karyotypes, and only 2 ofthose had other sonographically detected abnor-malities besides EIF. More recently, Wax and colleagues125 correlated an increased risk of ane-uploidy with the conspicuity of EIF. Our ownobservations agree that multiple or unusuallyprominent EIF appear to carry a greater risk.

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Figure 9. Trisomy 21 and EIF. Apical 4-chamber view of the heart at 17 weeksshows EIF (arrow) in the left ventricle of the heart. It was the only sonographicabnormality in this case.

Mild Ventricular Dilatation

The size of the lateral ventricles remains rela-tively constant throughout gestation, with amean diameter of 6.1 ± 1.3 mm and slightlylarger ventricles in male than in female fetuses(6.4 versus 5.8 mm).126 Ventriculomegaly is sus-pected when the atrial diameter reaches 10mm, although separation of the dependentchoroid from the medial ventricular wall maybe visible evidence of early ventricular dilata-tion.127

Mild ventricular dilatation deserves commentbecause it has been associated with trisomy 21as well as other aneuploidies.128–130 Althoughsome authors40,41 have categorized it as a majorabnormality, we think it shares similar charac-teristics (nonspecific, common in normalfetuses, and often transient)131 with otherminor markers. It is more likely to be seen as anormal variant later in the second trimester(after 20 weeks) and in male fetuses.

In a series by Bromley et al,129 12% (5 of 43) offetuses with mild ventriculomegaly (ventriculardiameter, 10–12 mm) had abnormal karyotypes(3 trisomy 21 and 2 trisomy 18), although all ofthese had other findings. Similarly, in our mostrecent series of trisomy 21, mild cerebral ven-tricular dilatation was observed in 4.3% (8 of186) of affected fetuses, but all had other find-ings, including structural defects (n = 3), 3 ormore minor markers (n = 3), or nuchal thicken-ing alone (n = 2).

On the other hand, Pilu et al130 evaluated 31fetuses with isolated borderline ventriculardilatation (10–15 mm) and found 3 with aneu-ploidy (2 with trisomy 21 and 1 with trisomy13). In a review of the literature including theirown cases (n = 234), chromosomal aberrations,mostly trisomy 21, were observed in 3.8%.Vergani et al132 evaluated 82 cases of mild ven-triculomegaly (10–15 mm) and found aneu-ploidy in 2 cases, both of which were associatedwith advanced maternal age. Seven additionalcases of aneuploidy were associated with otheranomalies. Current experience suggests thatmild cerebral ventricular dilatation increasesthe risk for fetal aneuploidy, although this riskremains difficult to determine. Further studiesare needed, including studies comparing ven-tricular measurements of fetuses with trisomy21 and normal fetuses.

Choroid Plexus Cysts

Although an association between choroid plexuscysts and trisomy 18 has been clearly estab-lished, a possible link with trisomy 21 has beencontroversial.133 Among 1346 fetuses with isolat-ed choroid plexus cysts reviewed by Yoder et al,27

5 had trisomy 21. The calculated likelihood ratiofor trisomy 21 was 1.87, but this did not reachstatistical significance (P = .16). Our own analy-sis suggests that choroid plexus cysts are statisti-cally more likely in fetuses with trisomy 21 butnot as isolated findings. We think that as an iso-lated finding after high-quality sonography, andassuming the patient is otherwise considered atlow risk for fetal aneuploidy, detection ofchoroid plexus cysts should not alter obstetricmanagement.

Reduction of Risk in Women OtherwiseConsidered at High Risk

Increasingly, normal sonographic findings areused to help reduce the risk of Down syndromefor women who otherwise would be consideredat risk for fetal trisomy 21.73,102,134 Reduction ofrisk is most useful for women in an intermediateage group, 34 to 40 years, and for women withintermediate risk based on biochemical screen-ing (risk 1:100). To what degree the risk is reduceddepends on a variety of factors, including thenumber and type of criteria used, individualthresholds, and, undoubtedly, the gestational ageat the time of scanning. Despite differencesamong centers, most recent studies (Table 5)suggest that a likelihood ratio in the range of 0.3to 0.4 can be assigned to a normal sonographicfinding. These likelihood ratios correspond to a60% to 70% reduction of risk. With the use of alarger number of criteria or a higher threshold,sensitivity of sonography approaching 90% hasbeen reported. Vintzileos and colleagues102 useda large number of SMFA but applied them only toreduce the risk among low-risk patients.

Comparison of Sonography and BiochemicalAnalysis

How does second-trimester sonography com-pare with second-trimester biochemical screen-ing? Surprisingly little data are currently availableregarding this.62,135 It appears that the reported

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sensitivity for sonography in detecting Downsyndrome at centers that have high-risk patientsis similar to that of second-trimester biochemi-cal screening. Considering the maternal age dis-tribution at the centers with high-risk patientsthat have reported results, the false-positiveresults of sonography are also similar to those ofbiochemical screening. One difference is thatnegative serum biochemical test results canreduce the risk much more than can normalsonographic findings. Also, biochemical testingis more widely available than high-qualitysonography.

It now seems clear that a combined risk esti-mate using both sonography and biochemicaltesting will be more effective than either alone. Acombined risk would also be less confusing thancompeting results from each. To date, however,few studies have evaluated the effectiveness ofcombining sonography and biochemicalscreening in the second trimester,136,137 eventhough a large number of reports haveaddressed this combined risk for the firsttrimester. Roberts and colleagues138 found thatsonography improved detection over that of second-trimester biochemical screening alonefrom 65% to 80%. Bahado-Singh et al139 havealso shown that incorporation of humeruslength and nuchal thickness significantlyimproves the receiver operator curves of bio-chemical risk assessment alone. Addition ofinhibin to the standard triple-marker test wouldfurther increase second-trimester detection oftrisomy 21 to 75% on the basis of biochemicalscreening alone.140,141 Optimal sonographic riskassessment will require computer calculationsusing risk estimates from multiple-of-the-mediandata from specific measurements (e.g., nuchalthickening and limb length).

In another development, urinary biochemicalmarkers may also prove to be effective in thedetection of trisomy 21. Bahado-Singh and col-leagues142 have reported that urinary hypergly-cosylated human chorionic gonadotropin (hCG)is superior to the 3 analytes of the triple-markerscreen. In 1 study, urine hyperglycosylated hCGwas combined with urine β-core fragmentserum α-fetoprotein and maternal age to yield adetection rate of 96% with a 5% false-positiverate or 94% sensitivity with a 3% false-positiverate.143 Incorporation of sonographic biometricmeasurements with urinary analytes further

improves screening performance. Using sono-graphic measurements of humeral length andnuchal thickness combined with hyperglycosy-lated hCG, Bahado-Singh et al144 found a 91.3%detection rate with a 3.2% false-positive rate.The area under the receiver operator curve was0.986 (P < .001), and that combination was supe-rior to hyperglycosylated hCG plus age alone orany other second-trimester screening protocol.

The Future

First-trimester nuchal translucency screeningand biochemical markers have proved to beeffective for detection of fetal aneuploidy.145 Atthis time, it remains uncertain whether first-trimester screening is more effective than sec-ond-trimester screening and what the ultimaterole of second-trimester screening will be. Waldet al146 have proposed that the combination offirst-trimester nuchal translucency screeningwith both first- and second-trimester biochemi-cal screening might be able to achieve 85% sen-sitivity for trisomy 21 with only a 1%false-positive rate. If validated clinically, thisapproach would significantly lower the predic-tive value of second-trimester sonographicmarkers.147,148 On the other hand, Bahado-Singhand coworkers139,144 have shown that sono-graphic markers can also be correlated with second-trimester biochemical markers to pro-vide similar high detection rates. Only time willtell whether sonographic markers associatedwith aneuploidy during the second trimesterwill ultimately have the same interest they dotoday.

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