Use of genetic sonography for adjusting the risk for fetal Down syndrome

Systematic evaluation of ultrasound findings known to be associated with trisomy 21, at an appropriate gestational age, has been referred to as a genetic sonogram. A number of high-risk centers performing genetic sonography have reported detection of ultrasound abnormalities in the majority of fetuses with fetal Down syndrome. However, nonspecific markers are more commonly observed than structural abnormalities, which are detected in less than 20% of cases in a nonselected population. Also, the actual sensitivity of a genetic sonogram will depend on various factors including the markers sought, gestational age, reasons for referral, and of course the quality of the ultrasound. Appropriate use of a genetic sonogram can help to modify the risk of fetal Down syndrome by decreasing the risk when the ultrasound is normal, or increasing the risk when specific ultrasound markers are detected. The postultrasound risk can be estimated by applying specific likelihood ratios, reflecting the strength of individual markers, with the a priori risk based on maternal age alone, or combined with biochemical markers when known. We review this approach of age-adjusted ultrasound risk assessment for fetal Down syndrome and illustrate how the risk can be estimated. Individual sonographic markers are also discussed.     

产前超声指标评分法对胎儿18三体综合征的诊断价值

目的 探讨产前超声指标评分法对胎儿18三体综合征的诊断价值.方法 采用前瞻性方法对2004年1月至2009年12月在中山大学附属第一医院行产前超声筛查孕妇中,发现胎儿结构或软指标异常者行胎儿染色体核型检查,根据胎儿染色体核型分析结果,分为18三体组和非18三体组.对两组胎儿任一异常超声指标进行单因素logistic回归分析,分别计算各超声指标的阳性似然比(+LR).+ LR≥200的超声指标赋值3分,100≤+LR ＜200的超声指标赋值2分,+LR＜100的超声指标赋值1分.根据受试者工作特性( ROC)曲线,确定最佳诊断界值.结果 (1)符合入选标准孕妇共26 545例,产前超声检查可疑胎儿畸形或有超声软指标异常并接受胎儿染色体检查者共4044例,其中21三体93例,18三体59例,13三体19例,其他类型染色体异常134例,正常核型3739例.22 501例胎儿产前超声检查无异常,3985例胎儿出生后随访其结局也无异常,共计26 486例胎儿为非18三体组,59例18三体胎儿为18三体组.(2)18三体组59例胎儿均有2种及以上超声提示的结构异常,其中最常见为肢体异常(85％,50/59),其次是心脏畸形(83％,49/59)和中枢神经系统异常(75％,44/59).肢体异常中以重叠指最常见,心脏畸形中室间隔缺损最多见,中枢神经系统畸形中最常见为“草莓头”型.(3)经logistic回归分析,所有超声异常指标中可进入回归方程的是脉络膜囊肿、“草莓头”型、后颅窝池增宽、前脑无裂畸形、耳低置、室间隔缺损、左心发育不良综合征等16项,按照此16项超声指标的+LR值分别得出不同分值.(4)18三体组和非18三体组产前超声评分1分值分别为2％ (1/59)和2.549％(675/26 486),4分值分别为9％( 5/59)和0.215％ (57/26486),9分值分别为10％( 6/59)和0.004％( 1/26 486),10～16分值分别为32％ (19/59)和0.(5)以不同总评分值为超声诊断18三体征的截断值,计算出各分值的敏感度和特异度,ROC曲线下面积为0.999.以总评分4分为最佳诊断值,诊断18三体征的敏感度为0.966,特异度为0.997.结论 超声指标评分法对18三体综合征具有较好的诊断价值,以4分作为诊断18三体综合征截断值其诊断效价最高.     

Latent class analysis applied to patterns of fetal sonographic abnormalities: definition of phenotypes associated with aneuploidy.

The aim of the present study was to generate different latent variables that classify the major chromosome aneuploidies using frequency and patterns of fetal sonographic abnormalities in a large database. A total of 1867 fetuses with sonographic abnormalities recorded in a database at New England Medical Center from January 1995 to March 1998 were available for the statistical analysis. Included within this group were 61 aneuploid fetuses, including 11 with 45,X, 30 with trisomy 21, 14 with trisomy 18 and 6 with trisomy 13, 40 structural malformations and/or sonographic markers were detected in these 61 aneuploid fetuses. The ability of malformations and sonographic markers to generate different groups of phenotypes was evaluated by means of latent class analysis, using the 61 affected cases. Four different classes were generated with the hypothetical assumption that each of them could satisfactorily identify a respective fetal aneuploidy represented in the study group. Among 40 fetal malformations and/or sonographic markers, the most important findings in generating specific karyotypic groups were cystic hygroma (class 1), duodenal atresia (class 2), holoprosencephaly (class 3) and omphalocele (class 4), respectively. Accuracy of the classification was 72 per cent for Turner syndrome (class 1), 74 per cent for Down syndrome (classes 1 and 2), 88 per cent for trisomy 13 (class 3) and 93 per cent for trisomy 18. The frequency of associated malformations detected sonographically can help to define a phenotype that is likely to be representative of a specific aneuploidy. Before the definitive karyotype is available or, in cases in which patients refuse an invasive prenatal diagnostic procedure, this may improve antenatal clinical management.     

Second trimester ultrasound screening for chromosomal abnormalities

The use of prenatal ultrasound has proven efficacious for the prenatal diagnosis of chromosomal abnormalities. The first sonographic sign of Down syndrome, the thickened nuchal fold, was first described in 1985. Since that time, multiple sonographically-identified markers have been described as associated with Down syndrome. The genetic sonogram, involving a detailed search for sonographic signs of aneuploidy, can be used to both identify fetuses at high risk for aneuploidy and, when normal, can be used to decrease the risk for aneuploidy for a pregnancy when no sonographic markers are identified. Combining the genetic sonogram with maternal serum screening may be the best method of assessing aneuploidy risk for women who desire such an assessment in the second trimester. Trisomy 18, Trisomy 13, and triploidy are typically associated with sonographically identified abnormalities and have a high prenatal detection rate. The use of the described sonographic signs in low-risk women requires further investigation, however, patients at increased risk for aneuploidy due to advanced maternal age or abnormal serum screening can benefit from a genetic sonogram screening for sonographic signs of aneuploidy to adjust their baseline risk of an affected fetus.     

Minor sonographic signs of trisomy 21 at 15-20 weeks' gestation in fetuses born without malformations: a prospective study.

A prospective study was performed on 2119 pregnancies that underwent genetic amniocentesis. Indications for amniocentesis were either maternal age (> or =35) or triple-test results (risk> or =1/380). The study covered a 36-month period and assessed the prevalence of minor ultrasound markers both in fetuses with Down syndrome and normal control fetuses at 15-19 week' gestation. Only fetuses with normal karyotype or trisomy 21 were considered. Six minor sonographic markers were considered: nuchal thickness, pyelectasia, femur observed/expected and humerus observed/expected ratios, bowel echogenicity, and choroid plexus cysts. One or more ultrasound soft markers were present in 23 out of 33 fetuses with Down syndrome (70%) and in 572 out of 2069 normal fetuses (28%).     

Sonographic nuchal markers for Down syndrome are more common but less ominous in gestations with a male fetus

OBJECTIVE: A change in the normal male-to-female ratio has been reported in some autosomal trisomies (i.e., trisomy 21 or trisomy 18). The objective of the present study was to evaluate the male-to-female ratio in pregnancies with sonographic nuchal markers for Down syndrome. METHODS: The results of amniocenteses performed for isolated nuchal markers for Down syndrome were grouped by fetal sex and by maternal age. The male-to-female ratio in normal and trisomic gestations was compared. RESULTS: 584 fetal karyotypes were available for analysis. A significantly higher male-to-female ratio was observed. More affected gestations were observed in association with a female fetus. These differences were mainly attributed to the group of patients younger than 35 years that represents more than 80% of our study population. No difference was observed in pregnancies of patients older than 35 years of age. CONCLUSIONS: In patients younger than 35 years, sonographic nuchal markers for Down syndrome are more frequent (but apparently less ominous) in gestations with a male fetus. If the gender is known, counseling can be modified to include such differential risks.     

9例18三体综合征胎儿的产前诊断

目的探讨利用孕妇血清筛查和胎儿超声筛查进行18三体综合征胎儿产前诊断的有效性。方法对36例首诊主诉为产前筛查胎儿18三体高危、92例首诊主诉为胎儿超声有异常发现的孕18~32周孕妇共128例，进行羊膜腔穿刺羊水细胞培养、或脐血管穿刺脐血细胞培养染色体分析。结果128例胎儿核型中，9例为18三体综合征，2例为其它染色体异常，染色体异常发现率为8．59％（11／128）。首诊主诉为18三体高危发现18三体4例，异常发现率11．11％（4／36）；首诊主诉胎儿超声异常发现18三体5例，其它染色体异常2例，异常发现率7．61％，其中2例18三体合并有筛查高危和超声异常。结论孕妇血清生化指标筛查结合胎儿超声检查是产前检出18三体胎儿的有效筛查手段。     

Variable levels of mosaicism for trisomy 21 in a non-immune hydropic infant with chylothorax.

We report the first case of mosaic trisomy 21 with non-immune hydrops fetalis and bilateral chylothoraces. Prenatal fetal blood karyotype analysis of 15 fetal cells revealed a 46,XX karyotype. Aggressive prenatal management, including fetal thoracocentesis and pleuro-amniotic shunt, was performed. A clinical phenotype of Down syndrome was apparent after the gross oedema had subsided. Subsequent chromosome study of neonatal blood lymphocytes showed mosaic trisomy 21 with 23 per cent trisomic cells. Review of the initial fetal blood sample identified trisomy in 5 per cent of 134 cells. Follow-up study at five months showed no trisomy 21 in 100 cells. This case illustrates the variable levels of mosaicism manifest in the peripheral blood of an infant with obvious Down syndrome phenotype, and the limitation of cytogenetic analysis of peripheral lymphocytes alone in prenatal and postnatal detection of low levels of mosaicism.     

Sonographic diagnosis of Down syndrome in the second trimester

We report a sonographic sign consisting of increased skin or soft tissue thickening at the back of the fetal neck during the second trimester, which correlates well with the diagnosis of Down syndrome. Eight hundred consecutive sonograms were performed in conjunction with genetic amniocentesis where four fetuses had trisomy 21 (Down syndrome) by karyotype. Two or 50% had sonographic findings consistent with Down syndrome. Recently we described a retrospective series where 904 sonograms were performed at the time of amniocentesis and seven fetuses had trisomy 21 on cytogenetic analysis. The abnormal sonographic finding at the back of the neck was present in three of those seven cases. Combining these series, 1704 fetuses were examined and 11 cases of Down syndrome were diagnosed cytogenetically. Five of the 11 or 45% had an abnormal sonogram suggestive of Down syndrome. Two of these were patients undergoing sonography for ascertainment of dates at 16 weeks and submitted to amniocentesis solely on the basis of this sonographic finding.     

Nasal bone assessment in prenatal screening for trisomy 21

A small nose is a common facial feature of individuals with trisomy 21. Evidence based on radiologic, histomorphologic, and sonographic studies shows that nasal bone abnormalities are significantly more common in trisomy 21 fetuses than in euploid fetuses. These abnormalities, which include both nasal bone absence and short nasal bone length, can be detected by prenatal ultrasound. In this article we review the evidence and discuss the potential value of assessment of the fetal nasal bone in screening for trisomy 21.     

Screening auf Chromosomenanomalien und Fehlbildungen im 1. Trimenon

During the last 10 years several sonographic and biochemical first trimester markers with discriminative power to distinguish between normal and aneuploid pregnancies have been reported. The most powerful marker is the measurement of nuchal translucency which detects more than 70% of pregnancies affected by trisomy 21.The importance of the latest sonographic marker, absence of nasal bone, is less clear. Biochemical markers such as PAPP-A and free beta-HCG combined with maternal age result in similar detection rates as second trimester biochemical screening. Combined sonographical and biochemical screening is expected to detect more than 90% of Down syndrome pregnancies although large prospective trials are not yet published to confirm these estimations. Most important in 1. trimester screening is counselling involving both pre- and posttest counselling. For all 1. trimester screening strategies a favourable cost-effectiveness ratio has been calculated.     

Prenatal sonographic findings in 207 fetuses with trisomy 21

OBJECTIVE: The objective was to evaluate the contribution of second trimester ultrasound examination to the prenatal diagnosis of trisomy 21 in 207 fetuses with this aneuploidy. The type and frequency of abnormal sonographic findings were determined. Possible multiple malformation patterns, characteristic of trisomy 21 were sought. STUDY DESIGN: Singleton fetuses that had prenatal sonography during the second trimester, then underwent cytogenetic evaluation in our institution, made up the study population. The sonographic findings of 207 fetuses with trisomy 21 were analyzed. RESULTS: Between 1990 and 2004, fetal karyotyping was performed in 22,150 patients for different indications. An abnormal karyotype was diagnosed in 514 cases (2.3%); among them 207 fetuses with trisomy 21 were detected (40.3%). Abnormal sonography was seen in 63.8% of the cases. Structural anomalies were detected in 28.5% of the trisomy 21 fetuses, among them cardiac defects (15.9%), central nervous system anomalies (14.5%), and cystic hygromas (6.8%) were the most common. Of the minor markers, increased nuchal translucency (28%), pyelectasis (20.3%), and shorter extremities (8.7%) were common findings. CONCLUSIONS: Appropriate diagnosis of structural anomalies, looking for relatively easily detectable minor markers and incorporating fetal echocardiography into the second trimester sonographic protocol, may increase the contribution of mid-trimester ultrasound examination to diagnosing trisomy 21.     

Prenatal diagnosis in the first trimester of pregnancy

In the past 2 decades, the second trimester of pregnancy has been the most common time for prenatal diagnosis of fetal anomalies and chromosomal aneuploidies. More recently, screening for and diagnosis of chromosomal abnormalities are increasingly being performed in the first trimester. With improvements and technological advances in ultrasound, it is now possible to identify many fetal structural anomalies at 11 to 13 6/7 weeks' gestation. At 10 to 11 weeks' gestation, biochemical markers in serum-PAPP-A, free beta-hCG, AFP, and uE3-combined with sonographic measurement of nuchal translucency and the presence/absence of the nasal bone can achieve a Down syndrome detection rate of 97.5% at a false-positive rate of 5%. Structural anomalies of the central nervous system, and the cardiac, renal, and gastrointestinal tracts can now be diagnosed by either transabdominal or transvaginal scanning, achieving detection of up to 80% of CNS anomalies by 13 weeks' gestation. In future, the emphasis in prenatal diagnosis will likely be in the first trimester. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader should be able to explain the rationale for first trimester combined ultrasound and serum analyte screening for fetal Down syndrome, describe the fetal anatomic structures that can be seen and evaluated in the first trimester, provide patient counseling about the relative benefits of genetic amniocentesis versus chorionic villous sampling, and discuss the application of Doppler technology to the evaluation of a first trimester fetus.     

Sonographic Markers of Fetal Aneuploidy—A Review

The most effective sonographic marker of trisomy 21 and other chromosomal defects is increased nuchal translucency (NT) thickness at 11–14 weeks. Extensive studies over the last decade have examined the methodology of measuring NT, the development of the necessary algorithms for calculating the individual patient risk for trisomy 21 by NT in combination with maternal age and with various maternal serum biochemical markers, and the performance of this test. Another promising marker for trisomy 21, both in the first and second trimesters, is absence of the fetal nasal bone. There is also an extensive literature on the association between chromosomal abnormalities and a wide range of second trimester ultrasound findings. However, there are very few reports that have prospectively examined the screening performance of second trimester markers. This article reviews the association between sonographically detectable fetal abnormalities and chromosomal defects, and examines the value of incorporating these defects in screening policies.     

New ultrasonographic markers of aneuploidies: nasal bones

The ultrasound sign of the absence of nasal bones in aneuploidies is discussed. Among several skeletal abnormalities in trisomy 21 fetuses, the absence or delay in the development of the nasal bones has been described by radiological and histological studies. The finding of absent nasal bones is recognizable by prenatal ultrasound examinations in first- and second-trimester fetuses, and about two-thirds of fetuses with trisomy 21 reveal absent nasal bones. There is evidence that an appropriate technique is required to visualize the fetal nasal bones by ultrasound. As, from preliminary studies, the absence of nasal bones does not appear to be related to fetal nuchal thickness, the two signs could be combined in a single test for prenatal screening of trisomy 21 that seems to be very accurate.

Prenatal ultrasound studies have shown the absence of nasal bone visualization also in first-trimester fetuses affected by trisomy 18, Turner's syndrome and trisomy 9.     

A six year study of the antenatal detection of fetal abnormality in six Scottish health boards.

OBJECTIVE: To assess the sensitivity of prenatal diagnosis by ultrasound and biochemical methods, to evaluate the reasons for non-detection and to make appropriate recommendations. DESIGN: Six year observational study, during which biochemical screening for trisomy 21 was introduced and there was an increase in routine ultrasound scanning at 18-22 weeks. SETTING: Six health boards in Scotland. POPULATION: 264,481 pregnancies, of which 862 were terminated because of fetal abnormality, and 2123 delivered with prenatally detectable major fetal abnormalities. MAIN OUTCOME MEASURES: The prenatal detection of trisomies 13, 18 and 21, and 12 major structural abnormalities, which the average ultrasonographer with average skills using average equipment would be expected to detect. RESULTS: Serum biochemical screening improved detection of trisomy 21 from 33% to 57%. The detection rate for the major abnormalities was 62% (815/1320) and 73% (598/818) when the trisomies were excluded. 18-22 weeks scanning yielded a 92% detection rate. Of the 505 undetected cases, 15% declined prenatal screening, 46% were unscreened because they were ineligible for testing, unbooked, booked too late or scanned too early for a diagnosis to be made, 2% had findings suspicious of a chromosomal abnormality but testing was not undertaken and 37% had a negative scan at a gestation when the abnormality was potentially detectable. CONCLUSIONS: A policy of first trimester scanning followed by serum alpha-fetoprotein screening and additional scanning as clinically indicated is effective in detecting major structural abnormalities, but scanning at 18-22 weeks and serum biochemical screening for trisomy 21 improved the detection rates. Supervised training and adequate equipment are essential. Present prenatal diagnostic tests will not detect all abnormalities and patients must be made aware of this.     

Second-trimester prenatal screening for trisomy 21 using biochemical markers: a 7-year experience in one cytogenetic laboratory

BACKGROUND: Screening for trisomy 21 in the second trimester of pregnancy using biochemical markers is an established part of prenatal care in many developed countries. OBJECTIVE: The present study was aimed at determining the incidence of trisomy 21 and other chromosomal abnormalities in women undergoing prenatal chromosome analysis after a second-trimester biochemical screening. RESULTS: A total of 2832 karyotypes were analyzed following a positive second-trimester maternal serum screening (risk > or = 1/250) between 1998 and 2004. Thirty-nine cases of trisomy 21 and 40 other chromosomal abnormalities were detected. The positive predictive value was 1 in 73 karyotypes for trisomy 21 and 1 in 71 for the other chromosomal abnormalities. However, a temporal decline in the detection rate of trisomy 21 was noted, from 1/63 in 1998 to 1/221 in 2004. This change was attributable to an increasing number of pregnant women having first-trimester ultrasound nuchal translucency measurement. CONCLUSION: Given the fact that nuchal translucency measurement combined with first-trimester biochemical marker screening has a positive predictive value of trisomy 21 comparable to that obtained following second-trimester biochemical screening, we should question whether to move trisomy 21 screening by maternal serum markers from the second trimester to the first trimester in conjunction with nuchal translucency measurement. Furthermore, genetic counseling prior to the amniocentesis should discuss the relatively high probability that a chromosomal abnormality other than trisomy 21 may be identified. Copyright (c) 2006 John Wiley & Sons, Ltd.     

Ultrasound findings and multiple marker screening in trisomy 18

OBJECTIVE: To compare detection of trisomy 18 in the second trimester by ultrasound and multiple-marker testing. METHODS: A computerized genetics database was used to identify fetuses of 14-22 weeks' gestation who had comprehensive ultrasound examinations, multiple-marker screening tests (alpha-fetoprotein [AFP]), hCG, unconjugated estriol [E3], and trisomy 18 karyotype. A positive trisomy 18 screen was defined as AFP up to 0.75 multiples of the median (MoM), hCG up to 0.55 MoM, and unconjugated E3 up to 0.60 MoM. A risk of at least 1:190 defined a positive Down syndrome screen. Ultrasound abnormalities were diagnosed prospectively and were confirmed later by retrospective review of sonographic images. RESULTS: From 1988-1997, 30 trisomy 18 fetuses who had comprehensive ultrasounds and multiple-marker testing were identified. Twenty-one (70%) had abnormalities detected by ultrasound, of which the most common isolated finding was choroid plexus cyst. Eleven fetuses (37%) had positive trisomy 18 screens, and two had positive Down syndrome screens, for a total of 13 of 30 (43%) fetuses with positive multiple-marker screening tests. CONCLUSION: We found that ultrasound was more likely to be abnormal than multiple-marker screening tests in fetuses with trisomy 18 (70%) (95% confidence interval [CI] 54, 86 versus 43% CI 25, 61). However, combining the two testing methods yielded the highest detection rate (80% [CI 66%, 94%]).     

A de novo duplication of chromosome 21q22.11→qter associated with Down syndrome: prenatal diagnosis, molecular cytogenetic characterization and fetal ultrasound findings

ObjectivesTo present prenatal diagnosis and molecular cytogenetic characterization of de novo partial partial trisomy 21q (21q22.11 → qter) associated with clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus on prenatal ultrasound.Materials, Methods, and ResultsA 34-year-old gravida 2, para 1 woman underwent amniocentesis at 20 weeks of gestation because of fetal structural abnormalities on prenatal ultrasound. A level II ultrasound at 20 weeks of gestation showed polyhydramnios, clinodactyly and hypoplastic midphalanx of the fifth fingers, midface hypoplasia, and an intracardiac echogenic focus. Amniocentesis revealed an aberrant derivative chromosome 9, or der(9). Parental karyotypes were normal. Spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) analyses revealed that the der(9) contained a segment of chromosome 21 distal to chromosome 9q, and FISH analysis additionally showed that the distal subtelomeric region of 9q was not deleted. Array comparative genomic hybridization (aCGH) demonstrated a 14.8-Mb duplication of distal 21q encompassing the Down syndrome critical region (DSCR) but no genomic imbalance in the distal euchromatic region of chromosome 9. The karyotype was 46,XX,der(9)t(9;21) (q34.3;q22.11)dn. Polymorphic DNA marker analysis revealed the maternal origin of the aberrant chromosome. The pregnancy was subsequently terminated. A malformed female fetus was delivered with a characteristic phenotype of Down syndrome.ConclusionSKY, FISH and aCGH are useful in prenatal investigation of the nature of a de novo aberrant derivative chromosome. Partial trisomy 21q encompassing the DSCR may present characteristic Down syndrome features on prenatal ultrasound.     

Prenatal cytogenetic diagnosis in Spain: analysis and evaluation of the results obtained from amniotic fluid samples during the last decade

Chromosome abnormalities are one of the main causes of congenital defects, and establishing their frequency according to the different clinical indications for invasive procedure during pregnancy is especially important for genetic counselling. We analyzed the results of 29,883 amniotic fluid samples referred to our laboratory for cytogenetic studies from 1998 to 2009, which constitutes the largest series of cytogenetic analysis performed on amniotic fluid samples in Spain. The number of samples received tended to increase from 1998 to 2005, but after 2005 it decreased substantially. Cytogenetic results were obtained in 99.5% of the samples, and the detected incidence of chromosome abnormalities was 2.9%. Of these, 48.1% consisted of classical autosomal aneuploidies, trisomy 21 being the most frequent one. The main clinical indications for amniocentesis were positive prenatal screening and advanced maternal age, but referral reasons with highest positive predictive values were, excluding parental chromosome rearrangement, increased nuchal translucency (9.2%) and ultrasound abnormalities (6.6%). In conclusion, performing the karyotype on amniotic fluid samples is a good method for the detection of chromosome abnormalities during pregnancy. The number of cytogenetic studies on amniotic fluid has now decreased, however, due to the implementation of first trimester prenatal screening for the detection of Down syndrome, which allows karyotyping on chorionic villus samples. Our results also show that both ultrasound abnormalities and increased nuchal translucency are excellent clinical indicators for fetal chromosome abnormality.