TRISOMY 21

TRISOMY 21

METABOLIC AND GENETIC SCREENING 0095-5108/01 $15.00 + .OO TRISOMY 21 Second-Trimester Ultrasound Menachem H. Graupe, MD, C. Scott Naylor, MD, Naomi...

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METABOLIC AND GENETIC SCREENING

0095-5108/01 $15.00

+ .OO

TRISOMY 21 Second-Trimester Ultrasound Menachem H. Graupe, MD, C. Scott Naylor, MD, Naomi H. Greene, RDMS, RDCS, Dru E. Carlson, MD, and Lawrence Platt, MD

Trisomy 21, or Down syndrome is common and serious in its consequences to both the affected individual and the family. As the most frequent autosomal chromosomal syndrome in humans, it is seen in 1 in 800 live births, and its overall incidence is even greater when all conceptions are taken into The first report of prenatal diagnosis of trisomy 21 occurred in 196fL7I Since that time, there has been constant work to improve the methods of identification and reduce the complications associated with early diagnosis. The initial, and most basic, screening test centers on the maternal age. Using the age 35 years at expected date of delivery identifies about 20% to 30% of affected fetuses. The associated false-positive rate is determined by the percentage of pregnant women above a given age (if 5% of pregnant women 38 In the are over 35 then the age of 35 has a false-positive rate of 5%).27, United States, all women who will be 35 years or older at expected date of delivery are offered prenatal diagnosis because of their increased risk of Down syndrome with increased maternal age. Most fetuses and subsequently most affected babies, however, are born to women less than 35 years old. Information about maternal age, history, multiple biochemical studies, and ultrasound findings can be combined to assess the chance of a fetus having an abnormal karyotype. Ultrasound screening for trisomy 21 in the second trimester involves correlating a large number of relatively nonspecific visual and biometric markers. Once the ultrasound From the Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California

CLINICS IN PERINATOLOGY VOLUME 28 * NUMBER 2 JUNE 2001

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examination is completed, the associated findings allow for more focused genetic counseling and can help guide decisions on whether to proceed with more invasive fetal testing (i.e., amniocentesis and chorionic villus sampling). With improved predictive value in screening tests, one strives to decrease and ultimately eliminate the need for invasive testing. Current second-trimester ultrasound screening has been shown to detect up to 60% of Down syndrome fetuses.25Ultrasound findings vary greatly in their correlation with trisomy 21. Many of the studies were done in women already considered at increased risk for aneuploidy to decrease the number of women undergoing karyotype analysis. Data were collected retrospectively and prospectively from patients who underwent a thorough ultrsound examination at the time of an amniocentesis, and those finding were then compared with the results of the karyotype analysis. As a result, much of our diagnostic information is derived from a high-risk population and may not be directly applicable to the general population. Although some of the sonographic abnormalities have a strong association with aneuploidy, most findings are also common in unaffected fetuses. When counseling the at-risk patient, one must take into consideration the sum of all available markers and not simply an isolated finding. This article reviews the various ultrasound markers that have been shown to be associated with increased risk of trisomy 21. HEADANDNECK

One of the earliest reported ultrasound markers for trisomy 21 was described by Benacerraf et a17as an increased nuchal skinfold thickness. Using a cutoff of 6 mm or greater, nuchal skin thickness has been reported in over 40% of fetuses with Down syndrome including 39% of fetuses without any other type of skin thickening8 Nuchal thickness should be measured on an axial view where the cavum septi pellucidi, cerebral peduncles, cerebellar hemispheres, and cisterna magna are seen (Fig. 1). The distance between the outer skull and skin surface should be measured three times with the largest consistent measurement used for evaluation.** Several meta-analyses have looked at the efficacy of the nuchal fold thickness measurement. Vintzileos and Egan73looked at 14 studies encompassing 249 diagnoses of trisomy 21 and found a sensitivity of 34% and a specificity of 99.5%. Wald et a175reviewed 16 studies, which included 390 fetuses with trisomy 21. Sensitivities ranged from 8% to 75% with specificity from 91.5% to 100%.Overall, Wald et a175calculated a sensitivity of 38% and specificity of 98.7% for the diagnosis of trisomy 21. There has been some question about the optimal time to do a nuchal skin measurement. Studies have evaluated nuchal thickness from 13 weeks to 24 but because of relatively small numbers of affected fetuses

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Figure 1. Ultrasound image of fetal head with thickened nuchal fold between calipers.

in each series, a single best age has not been identified. Ideally, the ultrasound examination should be done at an age at which a confirmatory diagnosis can be obtained and a safe termination can be offered. Gray and Crane37in their study of 32 fetuses with Down syndrome in 8138 pregnancies divided the population into two groups by gestational age. Using a 6-mm cutoff they noted an increase in the sensitivity in the 19- to 24-week group (versus the 14- to 18-week group) from 35% to 83% with a minimal corresponding decrease in specificity from 98.8% to 96.5%. Early suspicion of an abnormality can potentially lead to early diagnosis, which then provides the patient with more time to consider options and greater safety if a termination is elected. When a fetus with trisomy 21 is followed serially between 10 and 23 weeks of pregnancy, abnormal thickness in the nuchal skinfold resolves in 9% of fetuses and appears for the first time in 27% of cases in which there were multiple examinations. Mean nuchal thickness increased 1.8 mm over an average 3-week interval between examinations.18Following the course of any marker of trisomy 21 through a pregnancy is complicated by an increase in both elective and spontaneous abortion. There is an increased risk of fetal death in affected pregnancies, and once identified a large increase in terminations of pregnancyjO In both normal and trisomy 21 fetuses, the nuchal fold thickness increases with gestational age as the fetus grows. Measurements must be corrected effectively for fetal age. The difference between the observed and expected nuchal fold thickness on the basis of biparietal diameter can be used to readjust the probability of Down Even among women at high risk for aneuploidy, not all prospective trials have found nuchal skinfold thickness to be a reliable screening test for Down syndrome. There is still a need for testing centers to counsel patients based on institution-specific data because of lack of reproducibility of measurements between centers.32As with any diagnostic tool, usefulness of nuchal thickness is dependent of ability to obtain an accurate measurement. A high degree of concordance between observers

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has been shown when assigning fetal risk for Down syndrome within a particular diagnostic center.I7 Many researchers have investigated a possible relationship between cysts in the choroid plexus and trisomy 21 (Fig. 2). Care must be taken to distinguish data involving an isolated choroid plexus cyst with that of choroid plexus cysts in fetuses with additional abnormalities on ultrasound. In a review of 7617 patients, 210 cases of choroid plexus cysts were identified. No other abnormalities were seen in most (86%) of the patients. One of these 181 fetuses was subsequently diagnosed with trisomy 21.50In a multicenter review of choroid plexus cysts, 224 cases of isolated cysts were found during 18,437 scans. Five (2%) of these fetuses were found to have chromosomal abnormalities, but in each case there was associated at least one other risk factor.22Furthermore, a prospective study of 9100 patients noted 102 fetuses with at lease one choroid plexus cyst with 98 patients in whom this was the only marker seen on ultrasound. An abnormal karyotype was identified in four (4.1%) of these fetuses with the remainder either having a normal karyotype or being phenotypically normal at birth. The maternal age of the patients with the aneuploidy is not described, although the mean age of the patients-with a diagnosed fetal cyst was reported to be 29 years.43 In a large review, 658 fetuses with choroid plexus cysts were identified in 101,600 births. Overall, 2.1% of these had a chromosomal abnormality. When only isolated findings of choroid plexus cysts were separately analyzed, 0.5% were chromosomally abnormal. If the analysis was stratified by age, 0.36% of mothers below the age of 36 years were aneuploid, whereas 2.4% were older.26Another large review identified 473 fetuses with choroid plexus cysts among 32,053 midtrimester sonograms including 21 with an abnormal karyotype. The prevalence of choroid plexus cysts was 1.38% among normal karyotype fetuses and

Figure 2. Transverse image of fetal head with bilateral cysts in the choroid plexus.

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1.40% among fetuses with trisomy 21. Both of the fetuses in this study with trisomy 21 also had other abnormalities.20 Although the presence of an isolated choroid plexus cyst may not substantially increase the risk for trisomy 21, it should signal the need for a thorough search for other markers. It is important to note that neither size, persistence, nor bilaterality of a cyst served as a predictor of chromosomal abn~rmality.~~ Likewise, resolution of a cyst later in pregnancy does not return risk for aneuploidy to that from before the cyst was identified. The choroid plexus cyst in conjunction with any other sonographic finding or maternal risk factor should lead to discussion of further testing for chromosomal diagnosis.34,44 Hydrocephalus is another suspicious cerebral finding for trisomy 21. Mild cerebral ventriculomegaly (10 to 15 mm) has been used by several authors as a marker for trisomy 21. Benacerraf et all2 identified ventriculomegaly in 11%of male and 7% of female fetuses with trisomy 21. In a series of 82 patients with ventriculomegaly, 9 patients were aneuploid. Each of these cases was also associated with either advanced maternal age (two of nine), or other sonographic anomalies (seven of nine).72 Other reported findings in trisomy 21 mirror phenotypic findings of affected infants at birth. These include flattened facial profile with small recessed nose, low-set or shortened ears, cystic hygroma, and 70 Abnormal thickness in the nuchal reduced frontal lobe dimensions.61, fold, however, seems to be the single best marker for trisomy 21 in the second trimester fetus with sensitivity reported as high as 75% in one prospective studyzs CHEST

Findings in the chest cavity have also proved useful in identifying aneuploidy. Although there is general agreement of need for further evaluation when structural cardiac abnormalities are seen, how to proceed in the presence of isolated ultrasound markers is more controversial. Because chromosomal abnormalities have been identified in 5% to 13% of fetuses with cardiac abnormalities, cytogenetic diagnosis should be offered regardless of other sonographic findings. At birth, 45% to 50% of infants with Down syndrome have heart defects.75In the first and second trimester, the number is likely higher because of the increased risk of spontaneous abortion in fetuses with aneuploidy. The maximum detection rate for Down syndrome would be 50% if all cardiac abnormalities could be identified antenatally and followed with a chromosomal diagnosis. Isolated echogenic foci and pleural effusions have a less well-defined role in diagnosis of trisomy 21. In one review of 2102 infants with cardiovascular malformations, 271 (13%)were found to have karyotype abnormalities. This was compared with a series of 2328 control infants in whom two had abnormal karyotypes. In this series endocardia1 cushion defect was the most com-

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mon cardiac abnormality in trisomy 21 (6O%), but it rarely occurred as an isolated cardiac lesion YO).^^ In another series of 502 fetuses that were referred for cardiac evaluation after 16 weeks' gestation, 31 cases of cardiac anomalies were confirmed. Nearly half (15 of 31) were found to have an abnormal karyotype including six (19%) with trisomy 21. In the 14 cases of fetuses with both a cardiac anomaly and a noncardiac anomaly, 71% had an abnormal karyotype. In the remaining 17 cases with isolated structural cardiac abnormality 29% had a karyotype abnormality. The most commonly detected anomaly was the atrioventricular septal defect (Fig. 3).56 Early fetal heart failure has been proposed as a possible mechanism for the development of increased nuchal fold thickness. When looking at a series of fetuses undergoing invasive diagnostic procedures, an abnormally increased ductus venosus pulsatility index was found in 73% (8 of 11) of fetuses subsequently diagnosed with trisomy 21.16 Measuring the ductus venosus flow is not always easy, and may be more difficult than seeing static structural abnormalities. Because of the limited number of studies addressing this Doppler relationship to aneuploidy, there is simply not an adequate conclusion on whether or not it can provide an independent marker for Down syndrome. Echogenic,foci in the fetal heart were first described in 198762and their significance with regard to chromosomal abnormalities has not yet been fully explained. They appear as small discrete structures, near the papillary muscles of chordae tendinae, that move with valvular leaflets (Fig. 4). Their echogenicity is most often similar to that of bone. When aborted fetuses with echogenic cardiac foci are examined, intramyocardial calcifications surrounded by fibrotic tissue can be identified. No pathologic changes have been identified in chordae tendinae or myocardial cells. In addition, no pathomorphologic differences were seen between the calcification in cases in which chromosomal abnormality was diagnosed and those in which there was a normal karyotype.'j9In fact,

Figure 3. Image of atrioventricular septal defect in second-trimester fetus with trisomy 21.

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Figure 4. Transverse image of fetal chest with echogenic intracardiac focus in left ventricle.

in euploid fetuses echogenic foci do not seem to be associated with cardiac malformation or dysfunction. The incidence of echogenic foci varies; it ranges from about 6% in studies of fetuses described as at high risk for aneuploidy, to 3% in other studies of those described as low risk.76In low-risk populations with isolated intracardiac echogenic foci, the associated risk of karyotype abnormalities is low. In 381 pregnancies with documented echogenic foci, two had chromosomal abnormalities; one had an unbalanced translocation and the other trisomy 21 (0.2%).In higher-risk populations with intracardiac echogenic foci, the risk of karyotype abnormalities seems to be much higher. In 391 fetuses, 28 (7%) had chromosomal abnormalities with 23 of these being trisomy 21. In 13 (3.8%) of 340 the focus was isolated. Furthermore, when other sonographic abnormalities were also seen, 10 (20%) of 51 fetuses were found to have trisomy 21.19,49, 76 Frequency of echogenic foci has also been found to vary by maternal race. Prevalence of second-trimester foci in fetuses with black mothers was 6%, in white mothers lo%, in Asian mothers 30%, and for mothers in whom the race was not identified 11%in study involving almost 500 patients and 59 fetuses with echogenic intracardiac Interestingly, there were no cases of trisomy 21 detected in the study. Unfortunately, many of these studies fail to include maternal age, race, history, or biochemical screening into account when making the risk assessment.

ABDOMEN A number of ultrasound findings deserve mention in the secondtrimester screening sonogram. Duodenal atresia, omphalocele, pylectasis, ascites, two-vessel umbilical cord, and echogenic bowel have all been extensively examined in their relationship to karyotypic abnormalities.

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Early fetal heart failure as described previously may account for ascites and hydrops sometimes seen in fetuses with trisomy 21. The double bubble of duodenal atresia occurs in 5% of fetuses with Down syndrome. During development, the duodenal lumen is initially filled with epithelial cells; if the lumen fails to recannulize, then duodenal atresia occurs.51Duodenal atresia has been diagnosed as early as 14 weeks by ~ o n o g r a m When . ~ ~ seen, a fetus has a 30% chance of being affected; however, it is often not possible to identify dueodenal atresia until the third trimester.53 Echogenic bowel has been described as hyperechogenic abdominal content. It has been compared with the echodensity of fetal liver and bone (Fig. 5).39In a study by Deren et al3I that looked at 3838 midtrimester pregnancies, 5 of 34 pregnancies with echogenic bowel had trisomy 21 on karyotype analysis. They report echogenic bowel to have a sensitivity of 14.7%and a specificity of 98%. Another review by Soh1 et aF7of 2743 midtrimester pregnancies who had ultrasound examinations before undergoing amniocentesis found 55 fetuses with trisomy 21. In this study echogenic bowel had a sensitivity of 16.4% for Down syndrome with a specificity of 98.4%. In a review of 131 consecutive pregnancies with echogenic bowel 62 fetuses had no other visible anomaly and 7% of these, were found to have Down syndrome. The other 69% were accompanied by hydrops, nuchal edema, growth restriction, or at least one other marker or abnormality. Twelve percent of the fetuses with an additional finding were subsequently diagnosed with Down syndrome.68a In 1996, Slotnik and A b ~ h a m a dpublished ~~ a system that grades the relative echogenicity of bowel when compared with the density of adjacent fetal iliac crest. The study looked at 7432 ultrasounds and identified 145 pregnancies with echogenic bowel. In the 40 fetuses with bowel that was echogenic, but less echodense than the iliac crest, no cases of Down syndrome or cystic fibrosis were identified. In 81 cases

Figure 5. Fetus with pyelectasis (arrows).

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Figure 6. Transverse image of fetal abdomen with echogenic bowel (arrow). Bowel has similar echogenicity to fetal bone.

where the bowel was equally echodense to iliac crest, 2 cases of cystic fibrosis and 2 cases of Down syndrome were identified. Furthermore, when the bowel was more echodense than fetal iliac crest 5 cases of cystic fibrosis and 6 cases of Down syndrome were diagnosed (five of which were diagnosed prenatally) out of 24 fetuses with echogenic The kidney is another organ that should be examined closely in the second-trimester sonogram. Renal pyelectasis, defined as 4 mm or more dilatation in the anteropesterior plane of the renal pelvis, is another finding that has been associated with sonographic diagnosis of trisomy 21 (Fig. 6). Benacerraf et all1 found 210 fetuses with pyelectasis among 7400 patients. Seven (3%) of these fetuses had Down syndrome. When reviewing images of fetal kidneys of 44 fetuses who had been previously diagnosed with Down syndrome, one in four were found to have pyelectasis. Wickstrom et al,n in a prospective study of 7481 patients, found that isolated fetal pyelectasis was associated with nearly a fourfold increase in risk for Down syndrome, beyond that related to maternal age. The study by Deren et aP1 found pylectasis to have a sensitivity of 3% and a specificity of 99.4% for trisomy 21. Using the same definition Soh1 et aP7 found pylectasis to have a sensitivity of 1.9% for Down syndrome and 4.8% for any karyotypic abnormality, with a similar specificity. Yet, even in studies that did not find an association with isolated pyelectasis, the risk for Down syndrome was increased when the renal finding was found in combination with other markers.73 A single umbilical artery or two-vessel cord occurs in about 1% of all d e l i ~ e r i e s Although .~~ such a cord is associated with additional abnormalities, there has been no association shown with trisomy 21. A prospective study of 102 fetuses with a prenatal diagnosis of single umbilical artery found 58% of cases to be isolated and all these were found to have a normal karyotype. When other structural abnormalities

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were seen in conjunction with a single umbilical artery, chromosomal abnormalities were seen in 23% of fetuses. In 9 of these 10 aneuploid fetuses the left umbilical artery had not developed, whereas overall the left was absent in 70% of the

EXTREMITIES

Many investigators have also looked at femur and humerus length as a possible marker of underlying trisomy 21. The short stature of individuals with trisomy 21 has been primarily accounted for by decreased femur length. Femur length has been compared with expected length, biparietal diameter, and combined with humerus length in other comparisons.8,13, 29, 46, 55, 58 In the reviews by Wald et a175and Vintzileos and Egan73the pooled sensitivities of long bone measurements ranged from 22% to 37% with poor agreement between the two meta-analyses. Vintzileos and Egan73found that the ratio of biparietal diameter to femur length was the best long bone marker for Down syndrome (sensitivity 37% and specificity 94%) when examining 23 studies. In a similar review of 23 studies Wald et a175found that humerus length compared with expected length was the best predictor (sensitivity 37% and specificity 94.7%). The normal biparietal diameter to femur length ratio and its standard deviation decrease with menstrual age. In trisomy 21 there is a significantly higher ratio with increased deviation in advancing maternal age. Before 18 weeks, the relatively short femur may not be as good a marker of Down syndrome having lower sensitivity and specifi~ity.~~” Vintzileos et a174went a step further and measured four fetal long bones and compared their length with controls standardized on the basis of gestational age (determined by biparietal diameter). Femur, humerus, tibia, and fibula were measured in 493 normal fetuses and 22 with trisomy 21. The sensitivity of having at least one of the four bones shortened had a sensitivity of 64% and a specificity of 78%. The leg-to-foot ratio has been seen as an alternative way of selfreferencing a fetus to correct for gestational age. Although femur length is shortened when compared with gestational age, the foot length is not affected. In a high-risk population a femur-to-foot length ratio less than or equal to 0.9 had a sensitivity of 71% and a specificity of 89% for Down syndrome. By reducing the cutoff to 0.85 the sensitivity decreased to 15% and the sensitivity increased to 99Y0.~’ In the unique population of 11 twins discordant for Down syndrome the ratio of femur length to biparietal diameter or to expected femur length did not correlate with karyotype. Abnormal nuchal skin thickness, however, did statistically differentiate the chromosomal findings.48 Clinodactyly, hypoplastic midphalanx in the fifth finger, is a familiar feature of children with trisomy 21, which can be seen in a careful midtrimester ultrasound (Fig. 7).68Benacerraf et aP0,l4 demonstrated the

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Figure 7. Image of fetal hand with clinodactyly.

clinodactyly in the fetus and then prospectively identified it in seven of eight affected fetuses out of a series with more than 1000 normal fetuses. Goldstein et a136compiled biometric data in 173 karyotypically normal fetuses and established a linear correlation with gestational age to create a reference in screening future pregnancies. In the review by Deren et a131the fifth digit could be seen on over 90% of examinations. Clinodactyly had a sensitivity of 97% and a specificity of 97% for Down syndrome. The sandal gap toe is another morphologic feature seen in infants with trisomy 21 (Fig. 8). It has been mentioned in studies investigating 66 Because of the rarity of sonographic markers of Down this abnormality, the literature regarding its power as a marker is scarce.

Figure 8. Image of fetal foot. Note large sandal gap between first and second toes.

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ANATOMIC SCORE

With so many possible ultrasound markers and a huge range of specificity and sensitivity, it is clear that systematic analysis of findings negative and positive would be useful in evaluating overall risk for a particular fetus. Several authors have proposed grading or scoring systems to improve risk assessment. Carlson et aP3 noted a pattern in certain fetuses with increased amniotic fluid. In those fetuses with an amniotic fluid index of 24 or more who had abnormal hand posturing and any other structural abnormality there was a marked increase in aneuploidies. Abnormal hand posturing was described as clenched hands with overlapped fingers that did not open during 30 minutes of observation or hypotonic hand position with large separation between thumb and index finger. Of the 49 patients with hydramnios, 22 had visible anomalies and 27% of these were aneuploidy including two with trisomy 21. In the 27 with no visible anomaly or hand posturing there were no abnormal karyotype~.~~ Benacerraf6introduced a scoring system based on major and minor abnormalities. Two points are given for an abnormally thickened nuchal fold or a major anatomic abnormality and one point each for shortened femur, shortened humerus, pylectasis, and echogenic bowel. A fetus who accumulates two or more points is considered to be at high risk for trisomy 21 with a sensitivity of 81%. A prospective evaluation of a similar scoring system was done on 1076 patients in whom eight cases of Down syndrome were diagnosed. Using a sonogram scoring index of one or greater in a high-risk population, 62% of fetuses with Down syndrome were identified. By also including women over the age of 40 the sensitivity was increased to 75%.’’ By combining a sonographic score with maternal age, attempts have also been made to select women over the age of 35 who may be at a reduced risk for trisomy 21. By applying Bayes’ theorem to risk for trisomy at a given maternal age in a fetus with a sonographic score of zero, a modified risk was calculated. Using this method the probability of Down syndrome in a 42-year-old woman whose fetus has a score of zero is equal to that of 35-year-old women who has not had a sonogram.52This means that for a woman less than 42 years old, with normal screening ultrasound, the risk of fetal trisomy 21 is less than that of a 35 year old and she should be counseled as such before invasive testing.” Sonographic markers have also been used in conjunction with various biochemical markers to improve the overall predictive value for trisomy 21. To determine whether nuchal skin thickness was an independent risk factor for Down syndrome, nuchal skinfold thickness was measured prospectively in 651 fetuses that had been referred because of an increased risk for Down syndrome (greater or equal to 1 in 270) based on maternal age and serum measurement of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol. In these patients, an abnormal nuchal thickness had a sensitivity of 50% and a

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specificity of 98.6%. When the risk through triple screen was greater than 1 in 270 but less than 1 in 100, a normal nuchal skinfold dropped the risk of Down syndrome 0 in 390 versus 8 in 253 fetuses.' Less data are available on the effectiveness of the triple screen combined with inhibin A (quadruple screen) and ultrasound. It seems that the addition of inhibin A further improves the sensitivity and specificity of 75 screening.30, Sonographically derived knowledge of fetal sex can be important in assessing risk based on biochemical markers. Without karyotype, ultrasound is essential for gender identification. Hydronephrosis is more common in the male fetus; a female fetus with bilateral pyelectasis may have a greater risk of trisomy 21 than her male counterpart. Female fetuses with Down syndrome have increased human chorionic gonadotropin and decreased alpha-fetoprotein when compared with affected male 47 In a study combining urine beta-core fragment of human chorionic gonadotropin with an abnormal screening ultrasound a sensitivity of 77.8% with a specificity of 95.9% for Down syndrome was found.2When combined with maternal age and urine beta-core fragment level, the sensitivity increased to 85.7% with a specificity of 95.1Y0.~ The addition of a second urinary analyte further improved the screening process. When the ratio of urinary beta-core fragment to total estriol was used in conjunction with maternal age and nuchal thickness, a 92.3% sensitivity was achieved with a 95.5% specificity, and a 100% sensitivity was achieved if the specificity fell to a still respectable 94.8Y0.~ SUMMARY Not every aspect of sonographic examination reveals karyotypic abnormalities. Ultrasound examination of a fetus with trisomy 21 generally reveals normal amniotic fluid, normal placentation, and normal fetal growth. In addition, other chromosomal abnormalities have many of the same sonographic findings as Down syndrome, and many findings have a large overlap with phenotypically normal fetuses.60 The importance of second-trimester ultrasound screening for Down syndrome has remained great because of its ease of use and relative effectiveness. Trained sonographers can adjust the relative risk for trisomy 21 and alter the need for genetic amniocentesis. It is important that parents understand the limitations of a screening test and the risks and benefits of possible subsequent confirmatory testing. If a major structural abnormality is identified on ultrasound, karyotype determination should be considered. Nuchal tlvckness in the first or second trimester remains the most clinically useful marker for trisomy 21.24The predictive value of all the markers depends on the population studied and can be modified by a host of biochemical markers and historical factors. If fetal karyotype analysis could be performed without sampling through the uterus, prenatal diagnosis could be offered to all pregnant

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women, and screening would be ~nnecessary.’~ Despite its limitations, ultrasound will have an important role in prenatal diagnosis at least until isolating and testing fetal cells from maternal blood or other sources becomes practical and widely available. Whether used alone or in conjunction with additional biochemical or molecular serum markers, ultrasound is an important and powerful tool in prenatal genetic evaluation.

References 1. Bahado-Singh RO, Goldstein I, Uerpairojkit B, et a1 Normal nuchal thickness in the midtrimester reduces risk of Down syndrome in pregnancies with abnormal triplescreen results. Am J Obstet Gynecol 1733106, 1995 2. Bahado-Singh RO, Oz UA, Deren 0, et al: A new screening protocol combining urine beta-core fragment and ultrasonography for Down syndrome detection. Am J Obstet Gynecol 178:779, 1998 3. Bahado-Singh RO, Oz UA, Flores D, et a1 Nuchal thickness, urine beta-core fragment level, and maternal age for Down syndrome screening. Am J Obstet Gynecol 180:491, 1999 4. Bahado-Singh R, Oz U, Kovanci E, et al: A high-sensitivity alternative to ”routine” gemetic amniocentesis: Multiple urinary analytes, nuchal thickness and age. Am J Obstet Gynecol 180:69, 1999 5. Bazzett LB, Yaron Y, OBrien JE, et al: Fetal gender impact on multiple-marker screening results. Am J Med Genet 76:369, 1998 6. Benacerraf BR: The second-trimester fetus with Down syndrome: Detection using sonographic features. Ultrasound Obstet Gynecol 7147, 1996 7. Benacerraf BR, Barss VA, Laboda LA: A sonographic sign for the detection in the second trimester of the fetus with Down’s syndrome. Am J Obstet Gynecol 151:1078, 1985 8. Benacerraf BR, Gelman R, Frigoletto F D Sonographic identification of second-trimester fetuses with Down’s syndrome. N Engl J Med 3171371, 1987 10. Benacerraf BR, Harlow BL, Frigoletto FD: Hypoplasia of the middle phalanx of the fifth digit A feature of the second trimester fetus with Down’s syndrome. J Ultrasound Med 9:389, 1990 11. Benacerraf BR, Mandell J, Estroff JA, et al: Fetal pyelectasis: A possible association with Down syndrome. Obstet Gynecol 76:58, 1990 12. Benacerraf BR, Miller WA, Nadel A, et al: Does gender have an impact on the sonographic detection of second-trimester fetuses with Down’s syndrome? Ultrasound Obstet Gynecol 5:30, 1995 13. Benacerraf BR, Neuberg D, Frigoletto FD: Humeral shortening in second-trimester fetuses with Down syndrome. Obstet Gynecol 77223, 1990 14. Benacerraf BR, Osathanondh R, Frigoletto FD: Sonographic demonstration of hypoplasia of the middle phalanx of the fifth digit: A finding associated with Down syndrome. Am J Obstet Gynecol 159:181, 1988 15. Bianchi DW Prenatal diagnosis by analysis of fetal cells in maternal blood. J Pediatr 127847, 1995 16. Borrell A, Antolin E, Costaq D, et al: Abnormal ductus venosus blood flow in trisomy 21 fetuses during early pregnancy. Am J Obstet Gynecol 179:1612, 1998 17. Borrell A, Costa D, Delgado RD, et al: Interobserver variability of midtrimester fetal nuchal thickness. Eur J Obstet Gynecol Reprod Biol 7227, 1997 18. Borrell A, Costa D, Martinez JM, et al: Natural evolution of nuchal thickness in trisomy-21 fetuses. Obstet Gynecol 91:78, 1998 19. Bromley B, Lieberman E, Shipp TD, et al: Significance of an echogenic intracardiac focus in fetuses at high and low risk for aneuploidy. J Ultrasound Med 17127, 1998 20. Bromley B, Lieberman R, Benacerraf BR Choroid plexus cysts: Not associated with Down syndrome. Ultrasound Obstet Gynecol 8232, 1996

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