Ultrasonographic Diagnosis of Trisomy 18: Is It Practical in the Early Second Trimester?

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1 Ultrasonographic Diagnosis of Trisomy 18: Is It Practical in the Early Second Trimester? Laurence E. Shields, MD, Leslie A. Carpenter, MS, CGC, Karin M. Smith, RDMS, Hanh V. Nghiem, MD The objective of this paper was to determine the rate of prenatal detection of ultrasonographic abnormalities in fetuses with trisomy 18 during the early second trimester. Our prenatal diagnosis database (encompassing January 1987 to June 1996) was searched for all patients referred for prenatal genetic evaluation between 14 and 22 weeks of gestation and who were found to have a fetus with a trisomy 18 karyotype. The sonographic reports and films were evaluated for the presence or absence of fetal anatomic abnormalities. Thirty-five fetuses were identified with a mean age of 17.3 ± 2.0 (standard deviation) weeks. Thirty of the 35 (86%) had at least one detected abnormality. Most fetuses had more than one abnormality, with the mean number of abnormalities per fetus being three (range, 0 to 6). The most common abnormalities noted were persistent abnormal position of fetal fingers (89%); choroid plexus cysts (43%); abnormally shaped fetal head (strawberry or lemon) (43%); two-vessel umbilical cord (40%); cardiac defects (37%); intrauterine growth restriction (29%); omphalocele (20%); neural tube defects (9%); and cystic hygroma or lymphangiectasia (14%). Abnormalities of amniotic fluid volume (12%) and renal defects (9%) were seen less frequently. These data suggest that in the early second trimester, the time of most routine screening ultrasonographic examinations, most but not all fetuses with trisomy 18 have sonographically detectable anatomic abnormalities. The fetal hand appears to be abnormal in most early second trimester fetuses with trisomy 18, but the abnormality may be subtle and or unilateral. KEY WORDS: Ultrasonography; Trisomy 18; Fetus, hands. ABBREVIATIONS BPD, Biparietal diameter; HC, Head circumference; AC, Abdominal circumference; FL, Femur length; ACOG, American College of Obstetrics and Gynecology; AIUM, American Institute of Ultrasound in Medicine; IUGR, Intrauterine growth retardation; SD, Standard deviation; NTD, Neural tube defects; AV, Atrioventricular; LMP, Last menstrual period Received November 10, 1997, from the Department of Obstetrics and Gynecology, Division of Perinatal Medicine (L.E.S., L.A.C.), and the Department of Radiology, Division of Diagnostic Ultrasound (K.M.S., H.V.N.), University of Washington School of Medicine, Seattle, Washington. Revised manuscript accepted for publication February 9, Address correspondence and reprint requests to L. E. Shields, MD, Department of Obstetrics and Gynecology, Division of Perinatal Medicine, Box , University of Washington, Seattle, WA Trisomy 18 is the second most common autosomal trisomy with a prevalence of 1 in 8,000 births. 1 A variety of anatomic abnormalities involving almost all organ systems have been noted at the time of autopsy and during obstetric ultrasonography. 2 6 Previous reports detailing the sonographic findings in fetuses with trisomy 18 have noted that 80 to 85% have detectable abnormalities. 2,5,6 However, these reports have included gestational ages from 12 to 40 weeks. Many, if not most, pregnant women receive a screening ultrasonogram in the early second trimester, a time when many but not all fetal anomalies are detectable. 7 Therefore, when screened in the early second trimester the actual number of sonographically abnormal fetuses with trisomy 18 may be less than when all gestational ages are included. The purpose of this study is 1998 by the American Institute of Ultrasound in Medicine J Ultrasound Med 17: , /98/$3.50

2 328 TRISOMY 18 IN EARLY SECOND TRIMESTER J Ultrasound Med 17: , 1998 to report our experience with prenatal detection of ultrasonographic abnormalities in fetuses with trisomy 18 during the early second trimester. MATERIALS AND METHODS Our patient population consisted of all patients referred to the University of Washington Prenatal Diagnosis Center from January 1, 1987, to June 30, 1996, whose fetuses were between the age of 14 and 22 weeks gestation and the fetal karyotype obtained at the initial visit was trisomy 18. Sonographic examinations were performed using a variety of commercially available ultrasound machines over the 9.5 year study period. Both 3.5 and 5 MHz transducers were used. Ultrasonographic imaging included standard biometry measurements of BPD, HC, AC, and FL as well as fetal anatomic evaluation of the cerebral ventricles, posterior fossa, spine, four-chamber view of the heart, stomach, kidneys, and bladder in accordance with ACOG and AIUM criteria. 8,9 In addition to these anatomic structures, we attempted to evaluate the following structures in all cases: nuchal skin fold area, cerebellum, right and left ventricular outflow tracts, renal pelves, and extremities. Color flow imaging of the fetal heart was used when a heart defect was suspected on the basis of the four-chamber view and imaging of the outflow tracts. IUGR was defined as a difference of at least 10 days between the mean gestational age by ultrasonography and LMP dating. In cases of omphalocele the mean gestational age was calculated from the BPD and FL, and in cases of anencephaly it was calculated from the AC and FL. Both the sonographic reports and the films were evaluated for the presence or absence of fetal anatomic abnormalities. RESULTS of the fetal hands were present in 18 cases, with 16 having positional abnormalities of the fingers (89%). Fetal fingers were usually in a persistently clenched position. However, subtle but persistent overlapping of the fetal fingers also was noted (Fig. 1). In one fetus one of the hands was observed to be persistently clenched while the other hand had normalappearing, nonoverlapping fingers (Fig. 2). Persistent abnormal positioning of the fetal fingers and hands was found evenly distributed in those fetuses evaluated early (14 to 18 weeks) and in those that were seen later in gestation (19 to 22 weeks). After fetal hand abnormalities, choroid plexus cysts were the next most common abnormality (43%). In five of the 15 patients with choroid plexus cysts, this was the only detectable anomaly, and the mean gestational age of these fetuses was similar to that of the rest of the group (18.2 weeks). An abnormal cranial shape also was seen frequently (43%); of these, three were lemon-shaped and associated with NTD (9%), and 12 (34%) were classic strawberry-shaped heads (Fig. 3). 6 Five of the 35 (14%) had major central nervous system abnormalities (three NTD, one ventriculomegaly, one Dandy Walker malformation). Thirty-nine percent of the fetuses had two-vessel umbilical cords, and all had other anatomic abnormalities. The heart was documented as abnormal in 10 of 27 cases (37%). The most common cardiac abnormality was a ventriculoseptal defect (n = 7), and one case each was found of hypoplastic left heart syndrome, AV canal, and complex heart lesion (endocardial cushion defect and double outlet right ventricle). The heart was not believed to be adequately visualized in eight of the cases, four were less than 15 weeks gestation, and the other four Figure 1 Fetal hand at 16 weeks gestation shows overlapped third and fourth fingers, which persisted throughout the examination. Thirty-five fetuses (11 male, 24 female) with trisomy 18 were identified. The mean age at the time of evaluation was 17.2 ± 2.0 SD weeks. The mean age of the patients was 34 ± 8 years (range, 16 to 47 years). The indications for referral were advanced maternal age (50%), suspected fetal anomalies (29%), choroid plexus cysts (9%), abnormal maternal serum screening (9%), and other (3%). Thirty of the 35 fetuses (86%) had at least one sonographically detected abnormality. The mean number of abnormalities per fetus was three (range, 0 to 6). As expected, in the fetuses with anomalies, nearly all organ systems were involved. Detailed descriptions

3 J Ultrasound Med 17: , 1998 SHIELDS ET AL 329 Figure 2 Right and left hands of a fetus with trisomy 18 at 18 weeks gestation. The image on the left shows a normal fetal hand without overlapping fingers, whereas the image on the left, of the same fetus, demonstrates the hand in a clenched position, which persisted throughout the examination. fetuses were at or less than 16 weeks gestation. One of the fetuses without adequate visualization of the fetal heart was noted to have a ventriculoseptal defect at autopsy after an intact termination of pregnancy. Cystic hygroma (n = 2) or total body wall edema (n = 4) was noted in 17% of the cases. IUGR was a common finding, with 10 of 35 (29%) having mean gestational ages by ultrasonography that were 10 days or less than LMP dating. Abnormal amniotic fluid volume was noted in four cases (12%), one with oligohydramnios and three with polyhydramnios (two associated with omphaloceles and one with an NTD). Ureteropelvic junction obstruction was noted in three fetuses (9%); all cases were mild (< 1.0 cm) and associated with other anatomic defects. DISCUSSION In this study, limited to the time period in gestation when most screening ultrasonograms are obtained, we noted that most but not all fetuses with trisomy 18 have ultrasonographic abnormalities. This finding is similar to results of other series of ultrasonographic abnormalities in fetuses with trisomy 18 that were not limited to the early second trimester. 2,5,10 12 The most common abnormality noted was persistent abnormal position of the fetal fingers or a clenched fist. Postnatal as well as in utero series have noted a strong association between abnormal fetal hands and chromosomal abnormalities. 2,3,5,12,13 This finding appears to be a sensitive test for trisomy 18 as well as other chromosomal and nonchromosomal fetal abnormalities. 14 An abnormal fetal hand position was seen in almost 90% of the fetuses whose hands were evaluated, but two fetuses had normalappearing fetal fingers and one fetus had subtle persistent overlapping of the middle and fourth fingers of one hand with the other hand appearing normal. Although careful documentation of both hands in the open fetal position will not identify all abnormal fetuses, it requires little additional time to obtain a routine scan, 13 and this finding appears to have a high positive predictive value for detection of chromosomally abnormal fetuses. 2,12 14 Furthermore, detailed evaluation of both fetal hands and fingers may also improve the detection of otherwise sonographically normal fetuses. Unfortunately, in our series, four of the five patients with anatomically normal ultrasonograms did not have detailed autopsies, although one fetus had sonographically normal hands.

4 330 TRISOMY 18 IN EARLY SECOND TRIMESTER J Ultrasound Med 17: , 1998 Figure 3 Axial scan of the fetal cranium demonstrates a strawberry-shaped fetal head. The occitioparietal region is disproportionately wide relative to the narrow frontal region. This finding was seen in 34% of the fetuses in this study. IUGR is a common finding in fetuses with trisomy 18, seen in 51 to 79% of fetuses. 2,11,15 However, this finding is much more common after 24 weeks, in which case it is observed in 89% 2 to 100% 11 of cases. IUGR appears to be less common in fetuses of less than 24 weeks gestation. Nyberg and coworkers, 2 in a subset of 47 fetuses of less than 24 weeks gestation, noted that 28% had IUGR, which is nearly identical to the 29% we observed. Trisomy 18 is thought to affect fetal growth symmetrically, and all 10 fetuses with IUGR all had symmetric (BPD, AC, and FL) growth delay. The association between choroid plexus cysts and trisomy 18 has been well documented In our study, 43% of the fetuses had choroid plexus cysts, Table 1: Distribution of Fetal Anomalies by Organ System Organ System Number (%) Hands* 16 (89%) CPC 15 (43%) Strawberry skull 12 (34%) Two-vessel cord 14 (40%) Cardiac 10 (37%) Cystic hygroma 6 (17%) Central nervous system 5 (14%) Abdominal wall 5 (14%) *One or both hands in a persistently clenched position; the total number of fetuses evaluated was 18. Choroid plexus cyst. Only 27 of the fetuses were considered to have adequate views of the heart at the initial ultrasonographic evaluation, all 16 weeks gestation. and in five of the 15 patients this finding was the only abnormality noted, again confirming this observation. Unfortunately in only one of these cases was there adequate documentation of the fetal hands, but in that case the hands were reported to be normal. Since the most common abnormality we noted was an abnormal position of the fetal hands, it is likely that documentation of an open position of the fetal hand and use of maternal serum triple screen markers, which appears to identify 80% of fetuses with trisomy 18, 23,24 should reduce the number of patients with choroid plexus cysts who need invasive testing and reduce the number of undetected cases of trisomy 18. In summary, during the time at which most screening ultrasonographic examinations are performed (14 to 22 weeks), most but not all fetuses with trisomy 18 have ultrasonographic abnormalities. Additional evaluation of the fetal hands and fingers, which appeared to be our most sensitive marker and adds little time to the sonographic examination, 13 should also increase the detection of chromosomally abnormal fetuses. REFERENCES 1. Van Dyke DC, Allen M: Clinical management considerations in long-term survivors with trisomy 18. Pediatrics 85:753, Nyberg DA, Kramer D, Resta RG, et al: Prenatal sonographic findings of trisomy 18: Review of 47 cases. J Ultrasound Med 12:103, Kinoshita M, Nakamura Y, Nakano R, et al: Thirty-one autopsy cases of trisomy 18: Clinical features and pathological findings. Pediatr Pathol 9:445, Moore CA, Harmon JP, Padilla LM, et al: Neural tube defects and omphalocele in trisomy 18. Clin Genet 34:98, Bundy AL, Saltzman DH, Pober B, et al: Antenatal sonographic findings in trisomy 18. J Ultrasound Med 5:361, Nicolaides KH, Salvesen DR, Snijders RJ, et al: Strawberry-shaped skull in fetal trisomy 18. Fetal Diagn Ther 7:132, LeFevre ML, Bain RP, Ewigman BGF, et al: A randomized trial of prenatal ultrasonographic screening: Impact on maternal management and outcome. Am J Obstet Gynecol 169:483, American College of Obstetrics and Gynecology: Ultrasonography in pregnancy. ACOG Technical Bulletin 187:1, American Institute of Ultrasound in Medicine: Antepartum obstetrical guidelines. J Ultrasound Med 5:241, Benacerraf BR, Nadel A, Bromley B: Identification of second-trimester fetuses with autosomal trisomy by use of a

5 J Ultrasound Med 17: , 1998 SHIELDS ET AL 331 sonographic scoring index. Radiology 193:135, Hill LM, Marchese S, Peterson C, et al: The effect of trisomy 18 on transverse cerebellar diameter. Am J Obstet Gynecol 165:72, Benacerraf BR, Harlow B, Frigoletto FD: Are choroid plexus cysts an indication for second-trimester amniocentesis? Am J Obstet Gynecol 162:1001, Reiss RE, Foy PM, Mendiratta V, et al: Ease and accuracy of evaluation of fetal hands during obstetrical ultrasonography: A prospective study. J Ultrasound Med 14:813, Carlson DE, Platt LD, Medearis AL: The ultrasound triad of fetal hydramnios, abnormal hand posturing, and any other anomaly predicts autosomal trisomy. Obstet Gynecol 79:731, Dicke JM, Crane JP: Sonographic recognition of major malformations and aberrant fetal growth in trisomic fetuses. J Ultrasound Med 10:433, Furness ME: Choroid plexus cyst and trisomy 18. Lancet 2:693, Fitzsimmons J, Wilson D, Pascoe-Mason J, et al: Choroid plexus cysts in fetuses with trisomy 18. Obstet Gynecol 73:257, Chinn DH, Miller EI, Worthy LM, et al: Sonographically detected fetal choroid plexus cyst: Frequency and association with aneuploidy. J Ultrasound Med 10:255, Shields LE, Uhrich S, Easterling TR, et al: Karyotype analysis in the presence of choroid plexus cyst: Is there really any controversy? J Ultrasound Med 15:735, Porto M, Murata Y, Warneke L, et al: Fetal choroid plexus cyst: An independent risk factor for chromosomal anomalies. J Clin Ultrasound 21:103, Platt LD, Carlson DE, Medearis AL, et al: Fetal choroid plexus cyst in the second trimester of pregnancy: A cause for concern. Am J Obstet Gynecol 164:1652, Walkinshaw S, Pilling D, Spriggs A: Isolated choroid plexus cyst the need for routine offer of karyotyping. Prenat Diagn 14:663, Staples AJ, Robertson EF, Ranieri E, et al: A maternal serum screen for trisomy 18: An extension of the maternal serum screening for Down syndome. Am J Hum Genet 49:1025, Barkai G, Goldman B, Riles L, et al: Expanding multiple marker screeening for Down s syndrome to include Edward s syndrome. Prenat Diagn 13:843, 1991