Prenatal Detection of Fetal Trisomy 18 Through Abnormal Sonographic Features

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1 Article Prenatal Detection of Fetal Trisomy 18 Through Abnormal Sonographic Features Lami Yeo, MD, Edwin R. Guzman, MD, Debra Day-Salvatore MD, PhD, Christine Walters, RDMS, Donna Chavez, MS, Anthony M. Vintzileos, MD Objective. To describe the prenatal detection of fetal trisomy 18 through abnormal sonographic features and to determine the sensitivity of sonographically detecting fetuses with trisomy 18. Methods. All genetic and cytogenetic records of fetuses with trisomy 18 were reviewed retrospectively ( ). From these, singleton fetuses who had prenatal sonography at our unit were identified. The maximal numbers of individual abnormalities from 1 sonographic examination (not limited to type of organ system) were recorded. Each abnormality was classified as major, minor, or other, and each organ system was classified as abnormal only once, regardless of the number of individual abnormalities identified in that system. The sensitivity of sonography in detecting abnormalities of trisomy 18 was determined. Results. Of 38 fetuses identified with trisomy 18, all had 4 or more prenatally detected sonographic abnormalities (sensitivity of sonographic detection of fetuses with trisomy 18, 100%). The median number of abnormalities per examination was 8 (range, 4 19). Sonographically detected major abnormalities were cardiac (84%; n = 32), central nervous system (87%; n = 33), gastrointestinal (26%; n = 10), and genitourinary (16%; n = 6). Sonographically detected minor abnormalities were short ear length below the 10th percentile for gestational age (96%; n = 26/27), upper extremities and hands (95%; n = 36), lower extremities and feet (63%; n = 24), and face (53%; n = 20). Fifty percent (19 of 38) had choroid plexus cysts identified, but this was never an isolated finding. Conclusions. In experienced hands, the sensitivity of detecting fetal trisomy 18 on prenatal sonography is 100%, and all cases will have multiple anomalies visualized. Key words: fetal; prenatal detection; sonogram; sonography; trisomy 18. Abbreviations IUGR, intrauterine growth restriction Received December 4, 2002, from the Division of Maternal-Fetal Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School (L.Y., E.R.G., C.W., A.M.V.), and Institute for Genetic Medicine (D.D.-S., D.C.), St Peter s University Hospital, New Brunswick, New Jersey USA. Revision requested December 18, Revised manuscript accepted for publication February 6, Address correspondence to Lami Yeo, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, Division of Maternal-Fetal Medicine, University of Medicine and Dentistry of New Jersey Robert Wood Johnson Medical School, St Peter s University Hospital, 254 Easton Ave, Medical Office Building, Fourth Floor, New Brunswick, NJ USA. Trisomy 18 is the second most common autosomal trisomy, with a uniformly poor prognosis, being associated with profound neurologic damage and mental deficiency in neonates. Its prenatal diagnosis by detection of sonographic abnormalities with subsequent karyotype acquisition is important in counseling patients and providing prognostic information. Diverse anatomic malformations have been reported in almost every organ system in this autosomal disorder. 1 4 There are several studies that have described the types and frequencies of prenatal sonographic findings in fetuses with trisomy However, in most studies, descriptions of the normal content and detail of their routine prenatal sonographic examinations were not provided. Only 2 studies provided descriptions about the content of the sonographic examinations in detecting 2003 by the American Institute of Ultrasound in Medicine J Ultrasound Med 22: , /03/$3.50

2 Detection of Trisomy 18 Through Abnormal Sonographic Features trisomy 18. 4,7 In addition, all previous studies have found that 64% to 97% of fetuses with trisomy 18 have 1 or more detectable abnormalities on sonography. 2,4 7 Bundy et al 3 also found that 75% (9 of 12) of fetuses with trisomy 18 had 1 or more sonographic abnormalities, with most having only 1 or 2. Seoud et al 8 found 100% sensitivity of sonography for detecting fetuses with trisomy 18; however, this was not restricted to fetal structural anomalies but also included abnormal measurements. Given our routine practice of performing a thorough anatomic sonographic survey in all fetuses in our unit, we undertook this study to describe the prenatal detection of fetal trisomy 18 through abnormal sonographic features and to determine the sensitivity of sonographically detecting fetuses with trisomy 18 by using our routine standardized protocol for a prenatal anatomic survey. Materials and Methods All genetic and cytogenetic records of fetuses with karyotypically documented trisomy 18 from 1992 through 2002 were identified and reviewed retrospectively. Other means of ascertainment such as pathologic reports were not used. From these cases of trisomy 18, singleton fetuses who had prenatal sonography solely at our Antenatal Testing Unit were identified. All sonographic evaluations were performed by a sonographer and also by one of the Maternal-Fetal Medicine physicians at our institution using either an ATL Ultramark HDI 9, HDI 3000, or HDI 5000 machine (Philips Medical Systems, Bothell, WA) or an Acuson 128XP machine (Siemens Medical Solutions, Mountain View, CA). Institutional Review Board approval was granted for this study. In our unit, in addition to following American Institute of Ultrasound in Medicine guidelines, 9 all sonographic examinations also routinely target the following structures: head (not limited to only cerebral ventricles and posterior fossa), face and neck (including nuchal fold thickness and ear length), thoracic cavity, cardiac outflow tracts, aortic and ductal arches, abdominal cavity, all extremities and long bones (including both hands and feet), and genitalia. Prenatal sonograms of fetuses with confirmed trisomy 18 were reviewed for the presence of fetal anatomic abnormalities. All sonographic findings were prospectively identified at the time of actual scanning. The maximal numbers of individual abnormalities from 1 sonographic examination (not limited to type of organ system) were recorded. Although some patients may have undergone serial sonographic examinations, only the initial examination performed for each fetus was included in the analysis. Each abnormality was also classified as major, minor, or other. and each organ system was classified as abnormal only once, regardless of the number of individual abnormalities identified in that system. Major sonographic abnormalities of trisomy 18 were defined as cardiac (major congenital heart disease), central nervous system (choroid plexus cysts [only if associated with other major sonographic abnormalities], neural tube defects, abnormal intracranial anatomic characteristics, ventriculomegaly or hydrocephalus, and abnormal head shape such as strawberry 10 or lemon), gastrointestinal (omphalocele, diaphragmatic hernia, and anorectal atresia), and genitourinary (urethrovesical obstruction, abnormal kidneys or bladder, and abnormal genitalia). Minor sonographic abnormalities of trisomy 18 were defined as upper extremities and hands (clenched or closed hands and overlapping digits, contractures, and radial aplasia), lower extremities and feet (clubfeet, rocker-bottom feet, abnormal position or appearance of toes, and contractures), face (abnormal profile, micrognathia, hypotelorism, and cleft lip and palate), and ears (shortened ear length <10th percentile for gestational age). 11 Other sonographic abnormalities of trisomy 18 were defined as intrauterine growth restriction (IUGR), umbilical cord abnormalities (cyst and single umbilical artery), hydrops and pleural effusions, cystic hygroma, and amniotic fluid abnormalities (oligohydramnios and polyhydramnios). Intrauterine growth restriction was defined as estimated fetal weight below the 10th percentile for gestational age according to the formula of Hadlock et al, 12 abdominal circumference greater than 2 SD below the mean, or both. The sensitivity of sonography in detecting abnormalities of trisomy 18 was determined by standard statistical methods. Results Thirty-eight fetuses with confirmed trisomy 18 were identified. All had diagnoses either by prenatal amniocentesis after the sonographic exam- 582 J Ultrasound Med 22: , 2003

3 Yeo et al ination (84%; n = 32) or after birth (16%; n = 6). The median age of the patients was 37 years (range, years). The indications for referral are shown in Table 1. One patient began prenatal care late and was referred for her first sonographic examination because of size less than dates. The median gestational age at the time of sonographic examination was 20.1 weeks (range, weeks). Table 2 depicts the sonographic findings divided according to gestational age at the time of sonographic examination. All 38 fetuses had 4 or more individual prenatally detected sonographic abnormalities (sensitivity of sonographic detection of trisomy 18, 100%). The median number of abnormalities per examination was 8 (range, 4 19; Table 2). As depicted in Table 3, the overall sonographic detection rates for major abnormalities were cardiac, 84% (n = 32); central nervous system, 87% (n = 33); gastrointestinal, 26% (n = 10); and genitourinary, 16% (n = 6). The types and numbers of individual abnormalities under each major organ system heading are also shown in Table 3. In the 32 fetuses with major congenital heart disease, the most common cardiac abnormality was an atrioventricular canal defect (n = 13); 3 of these fetuses had the atrioventricular canal defect plus each of the following: pulmonic stenosis, transposition of the great vessels, and an abnormal cardiac axis. The remaining 19 heart abnormalities were ventricular septal defect (n = 6), complex heart defect otherwise unspecified (n = 5), atrial or ventricular septal defect (n = 3), hypoplastic left heart (n = 2), abnormal heart axis or position (n = 2), and coarctation aorta (n = 1). Sixteen fetuses had abnormal intracranial anatomic characteristics on prenatal sonography. These were posterior fossa abnormality or banana sign (n = 4), cerebellar hypoplasia (n = 4), Dandy-Walker variant (n = 2), dilated cavum septum pellucidum (n = 2), enlarged cisterna magna (n = 1), arachnoid cyst with obliterated cisterna Table 1. Indications for Referral to the Sonography Unit (38 Fetuses With Trisomy 18) Indication for Sonography n (%) Advanced maternal age 20 (53) Routine anatomic survey 13 (34) Abnormal triple screen results 4 (10) Size less than dates 1 (3) magna (n = 1), dysplastic brain with absence of normal intracranial structures (n = 1), and absent cavum septum pellucidum (n = 1). Thirty-nine percent (n = 15) of the fetuses had abnormal head shapes; of these, 26% (n = 10) had classic strawberry-shaped heads, 10 and 13% (n = 5) had lemon-shaped heads associated with neural tube defects. The 4 fetuses with sonographically abnormal kidneys and bladders had enlarged, echogenic kidneys bilaterally (n = 2), difficult visualization of the kidneys and small bladder (n = 1), and absent left and right kidneys low in the abdomen with pyelectasis (n = 1). One male fetus had hypospadias on prenatal sonography, whereas another had hypoplastic female genitalia with an anteriorly displaced anus. Fifty percent (19 of 38) of all fetuses with trisomy 18 had choroid plexus cysts identified, but this was never an isolated finding. Of these 19 fetuses, 79% (n = 15) had cysts located bilaterally, and in 6, the choroid plexus had a moth-eaten appearance. Four fetuses had unilateral choroid plexus cysts, of which 3 had only single cysts. As stated previously, all 38 fetuses with trisomy 18 had 4 or more individual prenatally detected sonographic abnormalities. When we excluded choroid plexus cysts in the count, all 38 fetuses (except for 1 fetus with 3) still had 4 or more individual prenatally detected sonographic abnormalities. As depicted in Table 4, the overall sonographic detection rates for minor abnormalities were upper extremities and hands, 95% (n = 36); lower extremities and feet, 63% (n = 24); face, 53% (n = 20); and shortened ear length, 96% (n = 26/27). Twenty-seven fetuses with trisomy 18 had prenatal ear length measurements available, which were defined as shortened if the ear length was below the 10th percentile for gestational age. 11 Table 4 also shows the types and numbers of individual abnormalities under each minor organ system heading. Ninety-two percent (n = 35) of all the fetuses with trisomy 18 had at least 2 of 4 minor abnormalities shown on sonography. The fetuses had any combination of 2 or more of the 4 (e.g., face and ear abnormalities, upper extremity and hand and lower extremity and foot abnormalities, and upper extremity and hand and ear abnormalities). One fetus had unilateral left radial aplasia with fixed hand deviation and absent thumb; both hands were clenched. J Ultrasound Med 22: ,

4 Detection of Trisomy 18 Through Abnormal Sonographic Features Table 2. Sonographic Features of Fetuses With Trisomy 18 (n = 38) Divided According to Gestational Age at the Time of Examination Case Gestational Age, wk Sonographic Features wk (6 cases) AVC, clenched hands, unilateral radial aplasia/fixed hand deviation, absent thumb IUGR, complex cardiac defect, NTD, large omphalocele, enlarged echogenic kidneys and bladder (posterior urethral valve), clenched hands, clubfeet, hypotelorism, short EL, cystic hygroma, anhydramnios Bilateral CPC, echogenic bowel, abnormal posturing limbs/clenched hands, pleural effusion, cystic hygroma IUGR, complex cardiac defect, absent CSP, banana sign, strawberry-shaped calvarium, small chest, omphalocele, absent stomach, overlapping digits, clubfeet, micrognathia, hypotelorism, short EL, ascites/skin edema, thick placenta, AEDV UA AVC, strawberry-shaped calvarium, clenched hands, left clubfoot, contracture of left leg, short EL Coarctation aorta, unilateral CPC, NTD, banana sign, lemon-shaped calvarium, overlapping digits, sloping forehead, micrognathia, short EL, pleural effusion, polyhydramnios wk (24 cases) 7 18 AVC, strawberry-shaped calvarium, omphalocele, clenched hands, short EL AVC, bilateral CPC, NTD, banana sign, lemon-shaped calvarium, clenched hands, clubfeet, rocker bottom feet, SUA IUGR, AVC, bilateral CPC, difficult visualization of kidneys, small bladder, overlapping digits, rocker-bottom feet, SUA, cystic hygroma ASD/VSD with enlarged aorta, bilateral CPC, lemon-shaped calvarium, small chest, clenched hands, unilateral clubfoot, rocker-bottom feet, cleft lip/palate, short EL IUGR, AVC, bilateral CPC, wrist contractures/clenched hands, lower extremity contractures IUGR, AVC, bilateral CPC, clenched hands, rocker-bottom feet ASD/VSD, unilateral CPC, ventriculomegaly/dangling choroid plexus, hypoplastic cerebellum, absent left kidney/right kidney low in abdomen with pyelectasis, clenched hands, rocker-bottom feet, abnormal feet/lateral deviation toes, flat profile, micrognathia, cleft palate, short EL and low-set ears, SUA, increased nuchal fold, 3 hyperechoic foci in left ventricle Hypoplastic left heart, clenched hands, short EL, SUA IUGR, hypoplastic left heart, contractures of upper extremities/clenched hands, contractures of lower extremities with clubfeet, hydrops, cystic hygroma IUGR, AVC, bilateral CPC, DWV, strawberry-shaped calvarium, clenched hands, clubfeet, contracture of left knee joint, short EL IUGR, bilateral CPC, strawberry-shaped calvarium, clenched hands, hypotelorism, short EL IUGR, VSD, bilateral CPC, brachycephaly, clenched hands, short EL Complex heart defect, omphalocele, clenched hands, micrognathia Complex heart defect, bilateral CPC, clenched hands with wrist contractures, clubfeet, contractures of lower extremities, micrognathia VSD, small cisterna magna, strawberry-shaped calvarium, clenched hands, abnormal facial profile, short EL, polyhydramnios IUGR, complex heart defect, bilateral CPC, DWV, omphalocele, absent stomach, clenched hands, short EL, SUA ASD/VSD, strawberry-shaped calvarium, clenched hands, rocker-bottom feet, hypoplasia mid face, short EL, SUA/straight cord, persistent RUV, polyhydramnios AVC, bilateral CPC, small stomach, left pyelectasis, clenched hands, clubfeet, flat facial profile, short EL, SUA, polyhydramnios IUGR, AVC, extreme levocardia, bilateral CPC IUGR, VSD, bilateral CPC, strawberry-shaped calvarium, clenched hands, rocker-bottom feet, short EL IUGR, VSD, unilateral CPC, cerebellar hypoplasia, clenched hands, rocker-bottom feet, abnormal facies, short EL IUGR, dysplastic brain/absence of normal intracranial structures, dextroposition with left diaphragmatic hernia, omphalocele, enlarged echogenic kidneys, clenched hands, postaxial polydactyly hands, rocker-bottom feet, dysplastic toes, left foot positioned backward, cyclopia/no nares/small mouth, short EL, pleural effusion IUGR, AVC, strawberry-shaped calvarium, overlapping digits, rocker-bottom feet, dysplastic toes (continued) 584 J Ultrasound Med 22: , 2003

5 Yeo et al Table 2. (continued) Case Gestational Age, wk Sonographic Features IUGR, VSD, unilateral CPC, dilated CSP, bilateral pyelectasis, clenched hands, abnormal profile with small nose, micrognathia, short EL wk (4 cases) Bilateral CPC, abnormal profile/midface hypoplasia, clenched hands, abnormal feet/hypoplastic toes, short EL IUGR, extreme levocardia, cerebellar hypoplasia, strawberry-shaped calvarium, diaphragmatic hernia, small stomach, clenched hands, short EL, polyhydramnios IUGR, AVC/pulmonic stenosis, clenched hands, clubfeet, rocker-bottom feet, short femur, hypotelorism, short EL IUGR, NTD, hydrocephalus/macrocrania, posterior fossa abnormality, lemon-shaped calvarium, omphalocele, clenched hands, clubfeet, severe lumbar lordosis wk (0 cases) wk (4 cases) IUGR, AVC/TGV, NTD, arachnoid cyst, obliterated cisterna magna, ventriculomegaly, lemon-shaped calvarium, clenched hands, clubfeet, short EL IUGR, dextroposition of heart, enlarged CSP, circular head shape, diaphragmatic hernia, hypoplastic female genitalia/anteriorly displaced anus, clenched hands, contractures of upper extremities/wrists, lower extremities jackknifed over fetus/left leg bent at knee in opposite direction, small feet/dysplastic toes, flat profile, micrognathia, hypotelorism, short EL, umbilical cord cyst, hydrops, polyhydramnios, absent stomach, AEDV/reversed flow in UA IUGR, VSD, enlarged cisterna magna, micrognathia, hypotelorism, short EL IUGR, cerebellar hypoplasia, anorectal atresia, hypospadias, clenched hands, upper extremity contractures, short foot length, abnormal position of toes, short femur, abnormal profile, hypotelorism, short EL, umbilical cord cyst, SUA, persistent RUV, venous complex on left side of abdomen, polyhydramnios AEDV indicates absent end-diastolic velocity; ASD, atrial septal defect; AVC, atrioventricular canal; CPC, choroid plexus cyst; CSP, cavum septum pellucidum; DWV, Dandy-Walker variant; EL, ear length; NTD, neural tube defect; RUV, right umbilical vein; SUA, single umbilical artery; TGV, transposition of great vessels; UA, umbilical artery; and VSD, ventricular septal defect. Table 3. Detection of Major Sonographic Abnormalities of Trisomy 18 by Organ System (n = 38) Organ System n (%) Cardiac (major congenital heart disease) 32 (84) Central nervous system 33 (87) Choroid plexus cysts* 19 (50) Neural tube defects 5 (19) Abnormal intracranial anatomic characteristics 16 (42) Ventriculomegaly/hydrocephalus 3 (8) Abnormal head shape (strawberry, lemon) 15 (39) Gastrointestinal 10 (26) Omphalocele 7 (18) Diaphragmatic hernia 3 (8) Anorectal atresia 1 (4) Genitourinary 6 (16) Urethrovesical obstruction 1 (4) Abnormal kidneys/bladder 4 (11) Abnormal genitalia 2 (5) *Included only if associated with other major abnormalities. Table 4. Detection of Minor Sonographic Abnormalities of Trisomy 18 by Organ System (n = 38) Organ System n (%) Upper extremities/hands 36 (95) Bilateral clenched/closed hands/overlapping digits 36 (95) Contractures 7 (18) Unilateral radial aplasia 1 (4) Lower extremities/feet 24 (63) Clubfeet 12 (32) Rocker-bottom feet 11 (29) Abnormal position/appearance of toes 6 (16) Contractures 5 (13) Face 20 (53) Abnormal profile (excluding micrognathia) 11 (29) Micrognathia 8 (21) Hypotelorism 7 (18) Cleft lip/palate 2 (5) Ear* 26 (96) *Defined as shortened ear length below the 10th percentile for gestational age; 27 had sonographic ear length measurements available; all fetuses with shortened ear length also had multiple other sonographic abnormalities. J Ultrasound Med 22: ,

6 Detection of Trisomy 18 Through Abnormal Sonographic Features As depicted in Table 5, the sonographic detection rates for other abnormalities were IUGR, 63% (n = 24); umbilical cord, 26% (n = 10); hydrops and pleural effusions, 13% (n = 5); cystic hygroma, 11% (n = 4); and amniotic fluid, 21% (n = 8). Of the 10 fetuses with cord abnormalities, 8 had single umbilical arteries, and 2 had umbilical cord cysts. Seven of the fetuses with amniotic fluid abnormalities had polyhydramnios, whereas 1 fetus had anhydramnios secondary to a posterior urethral valve. Discussion With current and improving high-resolution sonography and technology, imaging with attention to detail is certainly achievable. In this study, we found that in experienced hands, when performing a thorough anatomic sonographic survey as described, 100% of fetuses with trisomy 18 had multiple anomalies ( 4). This number of anomalies and sensitivity were much higher than what has been previously reported in most studies (Table 6). Over 10 years, to our knowledge, we have never had a neonate born with trisomy 18 that was not detected by our prenatal sonography. Although the sensitivity of prenatal sonography in detecting trisomy 18 has been previously reported as 100%, this was not restricted entirely to structural anomalies but also included fetuses with abnormal measurements. 8 We found that the sonographic presence of short ear length, bilateral clenched or closed hands or overlapping digits, and central nervous abnormalities were the 3 most sensitive markers for fetal trisomy 18. In a sample of 15 fetuses with trisomy 18, Benacerraf et al 13 found that 80% had 1 or more sonographic abnormalities (range, 0 5). Three of the fetuses had no sonographic findings at all; Table 5. Detection of Other Sonographic Abnormalities of Trisomy 18 (n = 38) Category n (%) IUGR 24 (63) Umbilical cord* 10 (26) Hydrops/pleural effusions 5 (13) Cystic hygroma 4 (11) Amniotic fluid 8 (21) *Eight had single umbilical arteries, and 2 had umbilical cord cysts. Seven had polyhydramnios, and 1 had anhydramnios due to a posterior urethral valve. however, these examinations were performed between 16 and 17 weeks. 13 In examining fetuses with trisomy 18 during the early second trimester only, Shields et al 4 found that most, but not all (86%; 30 of 35) fetuses had 1 or more detected abnormalities on sonography, with a mean number of abnormalities per fetus of 3 (range, 0 6). Salihu et al 6 found that of their 11 cases of trisomy 18, only 64% had prenatally detected sonographic anomalies, with polyhydramnios (n = 4) being the most commonly seen abnormality. Bundy et al 3 found that of 12 cases with antenatal sonograms available, the actual diagnosis of trisomy 18 was suggested antenatally only twice, and chromosomal studies were prompted by sonographic findings in only 4 cases. In 1993, Nyberg et al 2 found that when choroid plexus cysts were excluded, 83% of fetuses with trisomy 18 (39 of 47) had 1 or more sonographic abnormalities (range, 0 6) identified. In our study, even when we excluded choroid plexus cysts, all fetuses with trisomy 18 (except 1 fetus with 3) still had 4 or more sonographic abnormalities detected prenatally. In another study by Benacerraf et al, 5 they reported 1 or more major sonographic abnormalities (range, 0 5), excluding choroid plexus cysts, in 77% (20 of 26) of fetuses with trisomy 18 examined between 14 and 36 weeks gestation. We found short ear length, when measured, overall to be the most sensitive marker for trisomy 18 (96%). It is important to note, however, that this finding was always seen with multiple other anomalies and never in isolation (Table 2). In the previously mentioned studies, this anatomic feature was not counted as a sonographic marker for trisomy 18, 2 6 although lowset ears with an abnormal helix have been found to be one of the most frequent external anomalies (77%) in autopsy cases of trisomy In a recent study of fetal ear length, 32% (11 of 34) of fetuses with major chromosomal abnormalities had short ear lengths, and in 6 cases, this was the only sonographic finding. 17 Of the 4 cases of trisomy 18 in this study, 75% (3) had short ear lengths as well as other sonographic abnormalities. 17 Additionally, we found the appearance of bilateral clenched hands and overlapping digits to be highly sensitive (95%) and the second most common sonographic abnormality in fetuses with trisomy 18. This feature, however, again was always seen with multiple other sonographic anomalies 586 J Ultrasound Med 22: , 2003

7 Yeo et al Table 6. Summary of Trisomy 18 Cases Detected on Prenatal Sonography in the Literature Sensitivity Maternal Gestational of Sonography Most Common Age, y Age, wk in Detecting Sonographic Study n (Range)* (Range)* Trisomy 18, % Abnormality (%) Bundy et al (1986) IUGR (42) (21 42) (12 40) Benacerraf et al (1988) NA 22.7 ± Abnormal hands or feet (73) (15 35) Benacerraf et al (1990) ± ± Abnormal hands (38), (23 43) ( ) clubfeet (38) Nyberg et al (1993) IUGR (51) (15 45) (29 fetuses) >24 (18 fetuses) Seoud et al (1994) ± ± Flexion of hands (70), clubfeet or rocker-bottom feet (70) Salihu et al (1997) 6 11 NA 24 (7 fetuses) 64 Polyhydramnios (36) >24 (4 fetuses) Shields et al (1998) ± ± Abnormal position of fingers (89) (16 47) Grandjean et al (1998) NA 20 ± NA DeVore (2000) 7 30 NA 17.5 ± Structural cardiac defects (80) (14 23) Feuchtbaum et al (2000) NA NA 65 CPC (43) 142 NA NA 66 NA Brumfield et al (2000) CPC (43) This study Shortened ear length <10th (21 42) ( ) percentile (96) CPC indicates choroid plexus cyst; and NA, not available. *Mean ± SD or median given when available. Also includes 1 or more abnormal measurements, not just structural anomalies. Includes all aneuploidy categories, not just trisomy 18. and, importantly, was seen even at early gestational ages ( weeks). This has been documented on fetoscopic observation as early as 14 weeks. The authors of that report concluded that malpositioning of the fingers in trisomy 18 occurs some time between 12 and 14 weeks. 18 Another case series reported overlapping fingers sonographically at 13 weeks. 19 Our sensitivity of 95% is similar to the experience of Shields et al, 4 who found that the most common sonographic abnormality seen in fetuses with trisomy 18 was persistent abnormal positioning of fingers or a clenched fist (89%), and to that of Kinoshita et al, 1 who found overlapping fingers and flexion to be the most common external anomalies (84%) on autopsy. Many other studies have also found abnormal hands to be the most common fetal sonographic abnormalities in trisomy 18. 5,8,13 In a postmortem study of aneuploid cases, clenched fists were seen in 35% (11 of 31) of cases of trisomy 18 at autopsy. 20 Another study of sonographically diagnosed fetal wrist position abnormalities showed 32% (n = 7) to have trisomy We have never sonographically visualized open hands (full extension of all fingers in the same plane as the metacarpals) in fetuses that ultimately prove to have trisomy 18. Our sensitivity for hand abnormalities was not 100%, however, because 1 fetus was 36 weeks at the time of sonographic examination (the hands were difficult to visualize), and in the other case, the hands were not examined sonographically because of the patient s request to stop the examination. In both cases, however, delivery and autopsy ultimately showed bilateral clenched hands. We found almost two thirds of our fetuses with trisomy 18 to also have lower extremity or foot abnormalities. In a study by Nyberg et al 2 of 47 fetuses with trisomy 18, extremity abnormalities were found by pathologic examination, sonography, or both in 93% of fetuses, suggesting that J Ultrasound Med 22: ,

8 Detection of Trisomy 18 Through Abnormal Sonographic Features when trisomy 18 is suspected on the basis of other sonographic findings, the hands and feet should be specifically evaluated. It is important to note that many prenatal sonographic findings, when found in isolation (e.g., IUGR, shortened ear length, fluid abnormalities, 2-vessel cord, closed hands, and choroid plexus cysts), may not necessarily be indicative of aneuploidy and can be commonly seen in euploid fetuses. However, when visualized in the context of multiple sonographic abnormalities (as in our study), this considerably increases the risk for aneuploidy, such as trisomy 18. Therefore, in screening of low-risk populations, if isolated markers (other than increased nuchal fold thickness and structural anomalies) are seen, they should not be used as indications for amniocentesis testing. Most patients were scanned between 18 and 21 weeks, because we think that is the most optimal time to screen for all fetal anomalies (including cardiac defects). If a fetus is sonographically evaluated too early in gestation, anomalies may be undetected because of inadequate visualization of organs. It should also be noted, however, that scanning even later in pregnancy (e.g., the third trimester) can still be very beneficial and informative in detecting trisomy 18 sonographically (Table 2). In fact, in this study the fetus with trisomy 18 who had the most sonographic abnormalities (n = 19) was scanned at 34.1 weeks gestation. Scanning even in advanced gestational ages still provides the opportunity for prenatal invasive testing, counseling regarding prognosis, or both, with subsequent impact on pregnancy management such as modes of delivery and resuscitation. In our study, 92% of fetuses with trisomy 18 showed at least 2 of the 4 minor abnormalities on sonography. This fact emphasizes the importance of thorough prenatal sonographic examination of fetuses, with attention to fine detail in addition to examination of major organ systems. It also emphasizes that when there is suspicion of aneuploidy, examining these other minor areas and finding them to be abnormal may further increase one s suspicion. For example, in one study, the authors concluded that facial abnormalities, particularly when associated with other congenital abnormalities, and anomalies of the hands and feet represented indications for prenatal cytogenetic diagnosis. 13 We found that most fetuses with trisomy 18 had major congenital heart disease (84%) and central nervous system abnormalities (87%) on sonography. Our sensitivity for prenatally detecting major heart disease was much higher than that of most other studies, which reported varying sensitivities, such as 8%, 3 37%, 4 38%, 2 39%, 15 and 67%. 8 This may be attributable to the detail with which each fetal heart is examined sonographically at our institution. A recent study by DeVore 7 also found structural heart defects to be present sonographically in 80% of their cohort of fetuses with trisomy 18. Our finding is consistent with the knowledge that cardiovascular anomalies occur in most trisomy 18 cases. 1,22 Although ventricular septal defects are reported as the most common cardiovascular malformations in trisomy 18 autopsies 1,23 and have been documented as the most common types of sonographic cardiac abnormalities in trisomy 18, 4 we found that our most common prenatally diagnosed congenital heart defects to be in the atrioventricular canal (41%). Half of our fetuses with trisomy 18 had choroid plexus cysts, but these were always associated with multiple other sonographic abnormalities. These findings were similar to those of Seoud et al, 8 in which choroid plexus cysts were present in 50% of their group with trisomy 18; however, it is not clear what percentage of these were isolated. Shields et al 4 found a choroid plexus cyst prevalence of 43% in their population with trisomy 18, but in 33% (5 of 15), these were the only anomalies detected prenatally. Nyberg et al 2 also found 17% (2 of 12) of their fetuses with trisomy 18 to have isolated choroid plexus cysts without any other sonographic abnormalities. A meta-analysis found that the likelihood of trisomy 18 was 13.8 times greater (95% confidence interval, ) than the a priori risk in fetuses with isolated choroid plexus cysts diagnosed in the second trimester. 24 In contrast, we had no fetuses with trisomy 18 who had isolated cysts as the only abnormalities visualized on sonography. Recently, DeVore 7 also found the prevalence of choroid plexus cysts in their fetuses with trisomy 18 to be 53.3%, and when these cysts were isolated, they were not associated with trisomy 18. Snijders et al 25 found that with isolated choroid plexus cysts, the risk for trisomy 18 was only marginally increased; however, if 1 additional abnormality was found, the maternal age-related risk increased about 20 times (with 2 additional abnormalities found, the risk increased almost 1000 times). Therefore, to increase or decrease 588 J Ultrasound Med 22: , 2003

9 Yeo et al one s suspicion of aneuploidy, when choroid plexus cysts are visualized, we think a thorough, detailed examination of the remaining fetal anatomy needs to be performed to rule out other abnormalities. In our experience, if no other anomalies are found (especially when hands are open and ear length is normal), the risk of aneuploidy remains very low. Shields et al 4 also stated that because the most common sonographic abnormality found in their population of fetuses with trisomy 18 was abnormal positioning of the hands, it would be likely that documentation of an open hand, along with use of maternal triple screening, should reduce the number of patients with choroid plexus cysts who need invasive testing. In conclusion, knowledge of the types of sonographic anomalies seen in fetuses with trisomy 18 should lead to improved prenatal detection of these types of fetuses, with subsequent counseling and karyotypic diagnosis. Ultimately, this should provide important prognostic information. Normal findings from a thorough anatomic survey in experienced hands should decrease a patient s risk of trisomy 18, regardless of the presence or absence of choroid plexus cysts or abnormal triple-screen results, to an extremely low level sufficient to avoid genetic amniocentesis after appropriate patient counseling. References 1. Kinoshita M, Nakamura Y, Nakano R, et al. Thirtyone autopsy cases of trisomy 18: clinical features and pathological findings. Pediatr Pathol 1989; 9: Nyberg DA, Kramer D, Resta RG, et al. Prenatal sonographic findings of trisomy 18: review of 47 cases. J Ultrasound Med 1993; 2: Bundy AL, Saltzman DH, Pober B, Fine C, Emerson D, Doubilet PM. Antenatal sonographic findings in trisomy 18. J Ultrasound Med 1986; 5: Shields LE, Carpenter LA, Smith KM, Nghiem HV. Ultrasonographic diagnosis of trisomy 18: is it practical in the early second trimester? J Ultrasound Med 1998; 17: Benacerraf BR, Harlow B, Frigoletto FD. Are choroid plexus cysts an indication for second-trimester amniocentesis? Am J Obstet Gynecol 1990; 162: Salihu HM, Boos R, Schmidt W. Antenatally detectable markers for the diagnosis of autosomally trisomic fetuses in at-risk pregnancies. Am J Perinatol 1997; 14: DeVore GR. Second trimester ultrasonography may identify 77 to 97% of fetuses with trisomy 18. J Ultrasound Med 2000; 19: Seoud MA, Alley DC, Smith DL, Levy DL. Prenatal sonographic findings in trisomy 13, 18, 21 and 22: a review of 46 cases. J Reprod Med 1994; 39: Leopold GR. Antepartum obstetrical ultrasound examination guidelines. J Ultrasound Med 1986; 5: Nicolaides KH, Salvesen DR, Snijders RJ, Gosden CM. Strawberry-shaped skull in fetal trisomy 18. Fetal Diagn Ther 1992; 7: Lettieri L, Rodis JF, Vintzileos AM, Feeney L, Ciarleglio L, Craffey A. Ear length in secondtrimester aneuploid fetuses. Obstet Gynecol 1993; 81: Hadlock F, Deter R, Harrist R. Sonographic detection of abnormal fetal growth patterns. Clin Obstet Gynecol 1984; 27: Benacerraf BR, Miller WA, Frigoletto FD. Sonographic detection of fetuses with trisomies 13 and 18: accuracy and limitations. Am J Obstet Gynecol 1988; 158: Grandjean H, Larroque D, Levi S. Detection of chromosomal abnormalities: an outcome of ultrasound screening. The Eurofetus Team. Ann NY Acad Sci 1998; 847: Feuchtbaum LB, Currier RJ, Lorey FW, et al. Prenatal ultrasound findings in affected and unaffected pregnancies that are screen-positive for trisomy 18: the California experience. Prenat Diagn 2000; 20: Brumfield CG, Wenstrom KD, Owen J, Davis RO. Ultrasound findings and multiple marker screening in trisomy 18. Obstet Gynecol 2000; 95: Chitkara U, Lee L, Oehlert JW, et al. Fetal ear length measurement: a useful predictor of aneuploidy? Ultrasound Obstet Gynecol 2002; 19: Quintero RA, Johnson MP, Mendoza G, Evans MI. Ontogeny of clenched-hand development in trisomy 18 fetuses: a serial transabdominal fetoscopic observation. Fetal Diagn Ther 1999; 14: J Ultrasound Med 22: ,

10 Detection of Trisomy 18 Through Abnormal Sonographic Features 19. Lam YH, Tang MH. Sonographic features of fetal trisomy 18 at 13 and 14 weeks: four case reports. Ultrasound Obstet Gynecol 1999; 13: Isaksen CV, Eik-Nes SH, Blaas HG, Torp SH, Van Der Hagen CB, Ormerod E. A correlative study of prenatal ultrasound and post-mortem findings in fetuses and infants with an abnormal karyotype. Ultrasound Obstet Gynecol 2000; 16: Paluda SM, Comstock CH, Kirk JS, Lee W, Smith RS. The significance of ultrasonographically diagnosed fetal wrist position anomalies. Am J Obstet Gynecol 1996; 174: Moerman P, Fryns JP, Goddeeris P, Lauweryns JM. Spectrum of clinical and autopsy findings in trisomy 18 syndrome. J Genet Hum 1982; 30: Matsuoka R, Misugi K, Goto A, Gilbert EF, Ando M. Congenital heart anomalies in the trisomy 18 syndrome, with reference to congenital polyvalvular disease. Am J Med Genet 1983; 14: Yoder PR, Sabbagha RE, Gross SJ, Zelop CM. The second-trimester fetus with isolated choroid plexus cysts: a meta-analysis of risk of trisomies 18 and 21. Obstet Gynecol 1999; 93: Snijders RJ, Shawa L, Nicolaides KH. Fetal choroid plexus cysts and trisomy 18: assessment of risk based on ultrasound findings and maternal age. Prenat Diagn 1994; 14: J Ultrasound Med 22: , 2003