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ORIGINAL RESEARCH |
From the Division of Maternal-Fetal Medicine, The Center for Perinatal Health Initiatives, and the Division of Clinical Genetics, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School/St. Peter’s Medical Center, New Brunswick, New Jersey.
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Abstract |
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Methods: Down syndrome fetuses who had third-trimester ultrasound examinations between 25 and 41 weeks’ gestation were matched for gestational age with three controls each. Fetal structural anomalies, Down syndrome dysmorphology markers (abnormal facial profile, sandal gap, tongue thrusting, clinodactyly, or hypoplastic middle phalanx of the fifth finger), and abnormal long-bone biometry (femur, humerus, tibia, and fibula; femur length to biparietal diameter ratio; and femur length to abdominal circumference ratio were abstracted from the ultrasound reports. The fetal face, hands, feet, profile, and cardiac outflow tracts are routinely evaluated in our center.
Results: Seventeen fetuses with Down syndrome who had third-trimester ultrasound evaluations were identified. Anomalies included cardiac defects (five), tongue thrusting (three), clinodactyly (three), abnormal profile (three), sandal gap (two), and duodenal atresia (two). Of the 17 fetuses, at least one long-bone abnormality was found in 13, at least one structural or biometric anomaly was found in 15, and at least two abnormal findings existed in 11. Abnormal ultrasound findings, including structural anomalies, short bones, and Down syndrome dysmorphology markers, were more common in cases than in matched controls.
Conclusion: At least one abnormal ultrasound finding was present in 15 of 17 fetuses, and abnormal bone measurements or ratios were discovered in 13 of 17. Abnormal long-bone biometry at third-trimester ultrasound should raise the suspicion of fetal Down syndrome.
Several studies have suggested that second-trimester ultrasound can help detect fetuses with Down syndrome by identifying abnormalities such as structural anomalies,1–6 Down syndrome dysmorphology markers5 (abnormal facial profile, tongue thrusting, clinodactyly, hypoplasia of the middle phalanx of the fifth digit, or sandal gap), and abnormal biometry7 (femur length to biparietal diameter ratio [FL/BPD], short femur, short humerus, short tibia, and short fibula). Little information exists about the usefulness of these ultrasound markers of aneuploidy, especially bone biometry, when identifying fetuses with Down syndrome in the third trimester.
We conducted a matched case-control study to determine whether there are statistically significant sonographic findings in Down syndrome fetuses compared with controls. We also determined the efficacy of abnormal bone biometry alone and in combination with structural and Down syndrome dysmorphology markers for detecting fetuses with Down syndrome in the third trimester.
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Materials and Methods |
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Markers of Down syndrome were defined as follows: hypoplasia of the middle phalanx of the fifth digit, if significantly smaller than the middle phalanx of the fourth digit; clinodactyly, if the fifth digit was persistently curved with the hand in extension; tongue thrusting if, in the profile view, the fetal tongue protruded intermittently through the lips; abnormal profile, if the forehead was unusually flattened; and sandal gap, if fluid was present persistently around the great toe throughout the scanning period.
Each fetus with Down syndrome was matched with three non–Down syndrome controls. Our series included a twin pregnancy with monozygotic placentation in which both fetuses had Down syndrome. Controls chosen were the next three fetuses undergoing ultrasound examinations that included biometric and anatomic evaluations, with the exception of one twin pregnancy. Because of the timing of this patient’s examination, it was not possible to match this case with the next three cases, so the previous three cases were chosen. Newborn charts were reviewed to confirm infant normalcy. Controls were matched with each case based on gestational age (within 1 week) and plurality (singleton or twin), but not maternal age. Controls were not excluded if they had structural or biometric anomalies. The presence of twins in the case and control series introduced an intercluster dependence; therefore, we randomly excluded one case twin and three control twins during analysis.
We report the ultrasound findings for the cases and controls as abstracted from the ultrasound reports. Ultrasound images and videotapes were not reviewed for either group. Fetal long bones were identified as short if the bone measurement was less than or equal to the fifth percentile for gestational age, using the nomogram of Jeanty.8 The fetal FL/BPD was considered abnormal if it was less than or equal to the tenth percentile for gestational age, using the nomogram of Hohler and Quetel,9 and the femur length to abdominal circumference ratio (FL/AC) was considered abnormal if it was at or below the tenth percentile, using the nomogram of Hadlock et al.10
Clinical characteristics including maternal age, gestational age, median gravidity and parity, and indications for ultrasound, were compared between Down syndrome fetuses (cases) and normal fetuses (controls) using unpaired t test or 
2, as appropriate. We compared ultrasound findings between the groups with Fisher’s exact test. P < .05 was considered statistically significant.
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Results |
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presents the ultrasound findings in the 17 fetuses with Down syndrome. Only three fetuses (nos. 12–14) were known to have Down syndrome at the time of ultrasound examination. Abnormal karyotype was suspected at the time of ultrasound in ten other fetuses (nos. 1–6, 9–11) because of findings of structural fetal abnormalities (including Down syndrome markers) or abnormal biometry. Amniocentesis was offered in all ten cases, but was done in only four. Karyotype at birth was confirmed in all cases. One woman had monochorionic twins concordant for Down syndrome (no. 2).
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Seven fetuses (nos. 4, 6, 10, 12–14, 16) had ultrasound examinations in the second and third trimesters. Six of them had at least one finding on third-trimester ultrasound suggesting Down syndrome. All seven fetuses had sonograms between 19 and 22 weeks’ gestation in which bone measurements and ratios were normal. Down syndrome markers were specifically excluded in five because of maternal age greater than 35 years or a known diagnosis of Down syndrome. One fetus had mild pyelectasis in the second trimester that was not present in the third. The atrioventricular canal defect was identified at 28 weeks’ gestation. Two fetuses had normal long-bone measurements in the second trimester that dropped below the fifth percentile by 29 and 31 weeks’ gestation, respectively. Two fetuses had no evidence of Down syndrome markers in the second trimester, but when scanned in the third trimester, one proved to have an abnormal profile, sandal gap, and clinodactyly, and the other had tongue thrusting and clinodactyly. Four fetuses had more than one ultrasound examination in the third trimester. One (no. 2) had abnormal bone length at 31 weeks’ gestation that was not evident at ultrasound at 26 weeks’ gestation. In all fetuses who developed shortened long bones during the third trimester, at least two bones, most commonly the femur and humerus, were abnormally short.
When cases were compared with controls, women carrying Down syndrome fetuses were significantly older (mean ± standard deviation 33.8 ± 7.2 years, range 25–40, versus 27.0 ± 6.0 years, range 24–40; P < .001), but there were no significant differences between groups in gestational age at ultrasound examination, gravidity, or parity. Indications for third-trimester ultrasound among the cases included anatomy evaluation in six, growth in nine, and fetal echocardiography in two. Among controls, the indications were anatomy evaluation in 20, growth in 27, and fetal echocardiography in one. In our study population at Saint Peter’s Medical Center, 85% of the women were white and 10% were black.
Table 2 compares fetal structural and biometric abnormalities between the cases and controls. Trisomic fetuses were significantly more likely to have an abnormal FL/AC. The finding of any biometric abnormality, defined as short femur, short humerus, short tibia, short fibula, abnormal FL/AC, or abnormal FL/BPD, was associated with an increased risk of Down syndrome. Ten of 17 fetuses with Down syndrome had structural anomalies, including Down syndrome dysmorphology markers, compared with only two of 51 control fetuses (P < .001). One of the control fetuses had coarctation of the aorta and cystic hygroma, which was the only chromosomal analysis done in the control group. The other had bilateral talipes equinovarus. At least one abnormal ultrasound finding, including structural anomalies, Down syndrome dysmorphology markers, or biometric abnormalities, was seen in significantly more Down syndrome cases (14 of 17) than controls (19 of 51). The high number of false-positive results in the control group was due to inclusion of the two anomalous fetuses and abnormal FL/BPD. We detected at least two abnormal ultrasound findings in ten of 17 cases compared with three of 51 controls.
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presents the sensitivity and specificity of abnormal sonographic findings in detecting Down syndrome calculated from the frequencies presented in Table 2
. At least one abnormal finding (as the abnormal test) had the highest sensitivity (15 of 17). Given the high false-positive rate of FL/BPD (35%), we recalculated the sensitivity after excluding FL/BPD data; sensitivity was 13 of 17 (77%) and specificity was 48 of 51 (94%). The finding of one or more long-bone biometric abnormalities had a sensitivity of 71%.
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Discussion |
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Information on detection of Down syndrome in the third trimester is limited, but identification of Down syndrome fetuses in the third trimester is important. Some patients seek prenatal care late in pregnancy. Some women who have normal second-trimester ultrasound examinations develop fetal malformations found only by third-trimester ultrasound. Both of these groups might be at risk of fetal aneuploidy and might benefit from ultrasound examination. If aneuploidy is suspected or severe fetal malformations are found in the third trimester, patients often choose karyotyping to help decide about the pregnancy. This information is useful in postpartum management of infants with major structural anomalies, preparation for birth of an infant with special needs, and adoption. This study evaluated the usefulness of structural and long-bone biometric anomalies and Down syndrome markers in third-trimester fetuses.
Two studies reported findings in third-trimester fetuses with Down syndrome. Rotmensch et al11 reported 14 fetuses with 24 structural anomalies found between 24 and 28 weeks’ gestation, as part of a larger study that reported anomalies in Down syndrome fetuses between 9 and 28 weeks’ gestation. Nyberg et al1 described the abnormalities found in 12 of 15 fetuses, also as part of a larger study of Down syndrome detection. The most common abnormalities found in third-trimester fetuses in these studies were fetal hydrops in eight, duodenal atresia in eight, and cardiac defects in six. However, these studies did not assess Down syndrome markers or abnormal bone lengths. Only Nyberg et al1 reported the number of third-trimester fetuses that were normal sonographically (three of 15). In our study, we found a similar incidence of cardiac defects and lower incidences of duodenal atresia and fetal hydrops. These latter findings are likely due to small numbers in each case series. One series11 found one second-trimester Down syndrome fetus with echogenic lungs, as we did in the third trimester. Prospective studies are required not only to correlate our findings but also to evaluate the usefulness of ultrasound for identifying third-trimester Down syndrome.
Our series included seven patients who had ultrasound examinations in the second and third trimesters, five of whom had complete evaluations for Down syndrome. Six of seven had one or more abnormal third-trimester ultrasound findings despite normal second-trimester examinations. In addition, two third-trimester fetuses with shortened, but not abnormally short, bones (ie, greater than the fifth percentile for gestational age) were found to have Down syndrome dysmorphology markers when the fetal face, hands, and feet were evaluated. These findings suggest that some fetuses with Down syndrome might develop abnormal bone lengths only in the third trimester, and that the Down syndrome dysmorphology markers originally described in the second trimester (abnormal facial profile, sandal gap, tongue thrusting, hypoplastic middle phalanx of the fifth digit, and clinodactyly) might become more pronounced during the later stages of pregnancy. We included three subjects whose karyotypes were known at the time of ultrasound, which might be a source of bias. However, despite knowledge of the karyotype and looking specifically for Down syndrome markers, the results were not uniform. These findings suggest that the intrauterine phenotypes of Down syndrome fetuses are not uniform and might evolve over time.
We found that abnormal fetal biometry, including FL/AC and shortened long bones (femur, humerus, tibia, and fibula), is useful in the third trimester to identify fetuses at increased risk for Down syndrome. Unlike previous reports of biometric abnormalities in the second trimester,6 ours did not find FL/BPD measurements as useful in the third trimester as in the second because of the high false-positive rates among controls. This might be due to increasing difficulty in obtaining an accurate BPD measurement as pregnancy progresses. Excluding the FL/BPD data from our analysis did not dramatically reduce sensitivity (77%) but did increase specificity (94%).
We found that 14 of 17 fetuses had at least one ultrasound abnormality, and ten of 17 fetuses had at least two abnormal ultrasound findings. Although this is lower than the incidence of one or two abnormalities in Down syndrome fetuses reported in the second trimester,5 the present study was retrospective and, as such, not all examinations were targeted specifically for Down syndrome markers or long-bone biometry with fixed protocols. The controls also might not represent the normal population of fetuses because they were receiving ultrasound examinations in the third trimester. Therefore, sensitivity and specificity values might be less if the control population were representative of normal third-trimester fetuses.
The best combination for sensitivity and specificity included structural anomalies, Down syndrome dysmorphology markers, and short bones, and excluded FL/BPD measurements. Although these computations were based on retrospective data, this combination of markers yielded a sensitivity of 77%. Previously reported second-trimester sensitivities have been as low as 50,1 with most studies reporting sensitivities of 83–93%.2–5
We found that the efficacy of third-trimester ultrasound to identify fetuses with an increased risk of Down syndrome was similar to that of second-trimester reports. However, the ability of individual institutions to detect structural malformations, particularly cardiac defects and long-bone biometric abnormalities, in their own populations might be quite different from our experience. Additional prospective studies with strict protocols are needed to refine the ability of third-trimester ultrasound to detect fetal Down syndrome.
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Footnotes |
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Received April 17, 1998. Received in revised form September 30, 1998. Accepted October 22, 1998.
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References |
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2. Benacerraf BR, Neuberg D, Bromley B, Frigoletto FD Jr. Sonographic scoring index for prenatal detection of chromosomal abnormalities. J Ultrasound Med 1992;11:449–58.[Abstract]
3. Nadel AS, Bromley B, Frigoletto FD, Benacerraf BR. Can the presumed risk of autosomal trisomy be decreased in fetuses of older women following a normal sonogram? J Ultrasound Med 1995;14:297–302.[Abstract]
4. DeVore GR, Alfi O. The use of color Doppler ultrasound to identify fetuses at increased risk for trisomy 21: An alternative for high-risk patients who decline genetic amniocentesis. Obstet Gynecol 1995; 85:378–86.[Abstract]
5. Vintzileos AM, Campbell WA, Rodis JF, Guzman ER, Smulian JC, Knuppel RA. The use of second trimester genetic sonogram in guiding clinical management of patients at increased risk for fetal trisomy 21. Obstet Gynecol 1996;87:948–52.[Abstract]
6. Vintzileos AM, Egan JF. Adjusting the risk for trisomy 21 on the basis of second-trimester ultrasonography. Am J Obstet Gynecol 1995;172:837–44.[Medline]
7. Vintzileos AM, Egan JF, Smulian JC, Campbell WA, Guzman ER, Rodis JF. Adjusting the risk for trisomy 21 by a simple ultrasound method using fetal long-bone biometry. Obstet Gynecol 1996;87: 953–8.[Abstract]
8. Jeanty P. Fetal limb biometry. Radiology 1983;147:601–2.
9. Hohler CW, Quetel TA. Comparison of ultrasound femur length and biparietal diameter in late pregnancy. Am J Obstet Gynecol 1981;141:759–62.[Medline]
10. Hadlock FP, Deter RL, Harrist RB, Roecker E, Park SK. A date-independent predictor of intrauterine growth retardation: Femur length/abdominal circumference ratio. AJR Am J Roentgenol 1983;141:979–84.
11. Rotmensch S, Liberati M, Bronshtein M, Schoenfeld-Dimaio M, Shalev J, Ben-Rafael Z, et al. Prenatal sonographic findings in 187 fetuses with Down syndrome. Prenat Diagn 1997;17:1001–9.[Medline]
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