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%).     

中晚孕期18-三体综合征胎儿的超声特征

目的:研究中晚孕期18-三体综合征胎儿超声影像的变化。方法:回顾分析经羊膜腔穿刺、脐血管穿刺胎儿染色体分析确诊为18-三体的胎儿24例的临床资料和超声影像特征。结果:24例18-三体胎儿中,22例超声影像有变化,占全部病例的91.7%;最常见的超声变化是心脏畸形,共15例,占62.5%;其它常见的异常有脉络膜囊肿、脐带异常、肢体异常、宫内生长迟缓、脑室扩大、小脑延髓池扩大等;还可见颅骨变形、颜面裂、颈项皮肤增厚、消化道闭锁、腹壁缺损、膈疝、肾盂轻度积水、羊水过多等。结论:超过90%的18-三体胎儿中晚孕期可发现超声影像改变,中晚孕期胎儿超声检查是产前筛查18-三体胎儿的有效手段。     

Re-evaluation of risk for Down syndrome by means of the combined test in pregnant women of 35 years or more

OBJECTIVE: Evaluation of combined test in pregnant women 35 years of age and over to detect fetal Down syndrome. MATERIALS AND METHODS: The study population included 408 pregnant women of 35 years and over, who requested the combined test (nuchal translucency, PAPP-A, free beta hCG, maternal age, cut-off 1:250) before deciding whether to undergo amniocentesis. RESULTS: The test was positive in 66 women who then requested amniocentesis for fetal karyotype determination; the other women had a negative test and declined amniocentesis. False-positives increased with maternal age from 6.6% at 35 years to about 50% at 40 to 41 and 100% in women over 41. Six cases of Down syndrome and two cases of trisomy 18 were detected. Not a single case of Down syndrome or trisomy 18 was missed, and other chromosome abnormalities were detected as well. CONCLUSIONS: The application of the combined test reduced the need for invasive testing to only 14% of the studied pregnant population, without missing any of the fetuses with trisomy 21 or 18.     

First-trimester nuchal translucency measurement and echocardiography at 16 to 18 weeks of gestation in prenatal detection for trisomy 18

BACKGROUND: Trisomy 18, the second most common autosomal trisomy, has the highest incidence of congenital heart disease of all chromosomal abnormalities. This study assessed the use of nuchal translucency (NT) measurement and fetal echocardiography at 16 to 18 weeks of gestation in prenatal detection for trisomy 18. METHODS: Screening for chromosomal aneuploidy using fetal NT measurement was performed at 10 to 14 weeks of gestation. Detailed fetal echocardiography was performed at 16 to 18 weeks of gestation immediately before genetic amniocentesis for fetal karyotyping in singleton pregnancies with increased fetal NT thickness. RESULTS: Of the 3151 singleton pregnancies included in our study, 171 cases (5.4%) of increased (> or =3.0 mm) NT were noted. Fetal chromosomal abnormalities were identified in 22 (12.9%) of these pregnancies, including 9 with trisomy 21, 5 with trisomy 18, 4 with 45,X and 4 with unbalanced structural abnormalities. Major defects of the heart and the great arteries were identified in 13 (7.6%) of these pregnancies with increased NT. These included eight pregnancies that also had the diagnosis of chromosomal aneuploidy. Among the 22 fetuses with confirmed aneuploidy, all 5 fetuses with trisomy 18, 1 of the 4 fetuses with 45,X and 2 of the 9 fetuses with trisomy 21 had increased fetal NT thickness associated with abnormal fetal echocardiography findings. CONCLUSIONS: Screening for Down syndrome and cardiac defects using first-trimester fetal NT measurement in combination with fetal echocardiography at 16 to 18 weeks of gestation is a feasible and sensitive procedure for the prenatal detection of trisomy 18.     

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%]).     

Trisomy 21. Second-trimester ultrasound

Not every aspect of sonographic examination reveals karyotypic abnormalities. Ultrasound examination of a fetus with trisomy 21 generally reveals normal amniotic fluid, normal placentation, and normal fetal growth. In addition, other chromosomal abnormalities have many of the same sonographic findings as Down syndrome, and many findings have a large overlap with phenotypically normal fetuses. The importance of second-trimester ultrasound screening for Down syndrome has remained great because of its ease of use and relative effectiveness. Trained sonographers can adjust the relative risk for trisomy 21 and alter the need for genetic amniocentesis. It is important that parents understand the limitations of a screening test and the risks and benefits of possible subsequent confirmatory testing. If a major structural abnormality is identified on ultrasound, karyotype determination should be considered. Nuchal thickness in the first or second trimester remains the most clinically useful marker for trisomy 21. The predictive value of all the markers depends on the population studied and can be modified by a host of biochemical markers and historical factors. If fetal karyotype analysis could be performed without sampling through the uterus, prenatal diagnosis could be offered to all pregnant women, and screening would be unnecessary. Despite its limitations, ultrasound will have an important role in prenatal diagnosis at least until isolating and testing fetal cells from maternal blood or other sources becomes practical and widely available. Whether used alone or in conjunction with additional biochemical or molecular serum markers, ultrasound is an important and powerful tool in prenatal genetic evaluation.     

Sonographically measured nuchal skinfold thickness as a screening tool for Down syndrome: results of a prospective clinical trial.

Second-trimester sonographic measurement of nuchal skinfold thickness has been proposed as a potential screening tool for Down syndrome detection. The feasibility of this technique was tested in a prospective study of 3338 consecutive pregnancies at 14-21 weeks' gestation. A nuchal skinfold thickness of 6 mm or greater was identified in 47 fetuses (1.4%), 12 of whom proved subsequently by either amniocentesis or postnatal follow-up to have Down syndrome. The sensitivity of nuchal skinfold thickness for Down syndrome detection was 75% (12 of 16 cases). When adjusted for the incidence of Down syndrome in the general population (one in 710 births), the positive predictive value of nuchal skinfold thickness for Down syndrome detection was one in 13. The observed sensitivity, false-positive rate, and predictive value suggest that amniocentesis should be offered when a nuchal skinfold thickness of 6 mm or greater is observed between 14-21 weeks' gestation.     

Pseudocyst of the umbilical cord: prenatal sonographic appearance and clinical significance

OBJECTIVE: To assess the clinical significance of umbilical cord pseudocysts detected prenatally by sonography. METHODS: The prenatal sonographic findings, karyotype, and perinatal outcome in 13 fetuses with umbilical cord pseudocysts were reviewed retrospectively. RESULTS: Umbilical cord pseudocysts were diagnosed at a median gestation of 27 weeks (range 15-37). Pseudocysts were single in eight cases with cyst diameters ranging from 20 to 50 mm, and double in one case. In the remaining four cases, multiple small cystic masses measuring less than 8 mm were identified. Additional sonographic findings were noted in 11 cases; ten of these fetuses had prenatal karyotyping, which showed trisomy 18 in five cases, trisomy 13 in one case, and a 46,XX, inv ins(18;21) complement in one case. Among the seven chromosomally abnormal fetuses, umbilical cord pseudocysts were multiple in four fetuses and single in three. All chromosomally abnormal fetuses and two euploid fetuses with associated structural defects died in utero or in the neonatal period. There were no perinatal complications in either of the fetuses with isolated pseudocysts. CONCLUSION: The prenatal sonographic appearance of umbilical cord pseudocysts varied widely. These umbilical cord cystic masses were associated strongly with chromosomal disorders and structural defects, regardless of their sonographic appearance in utero.     

Fetal nasal bone and trisomy 21 in the second trimester

OBJECTIVES: To assess the feasibility of measuring nasal bone length in the second trimester of pregnancy and to confirm if fetal nasal bone absence or hypoplasia is a marker for Down syndrome. METHODS: Fetal nasal bone assessment was performed in 439 consecutive singleton pregnancies at high risk of Down syndrome between 15 and 21 weeks. All ultrasound examinations were performed transabdominally by five skilled sonographers. If the nasal bone was present, its length was measured. The biparietal diameter: nasal bone length ratio (BPD/NBL) was also calculated. RESULTS: Nasal bone assessment was successfully achieved in all fetuses. The nasal bone was absent in 2(0.47%) of the 417 unaffected fetuses and in 10(55.5%) of the 18 fetuses with trisomy 21. Of the 8 Down syndrome cases with a nasal bone present, 4 had nasal bone hypoplasia and 4 had a normal nasal bone. BPD/NBL was 9 or greater in 7 of the 8 fetuses affected by trisomy 21 with nasal bone present and in 86 (20.6%) of the 417 normal fetuses; it was 10 or greater in 5 of the 8 (62.5%) fetuses affected by trisomy 21 and in 41 of the 417 (9.8%) euploid fetuses. CONCLUSIONS: Nasal bone absence is a marker for Down syndrome in the second trimester of pregnancy. Inclusion of nasal bone length into the second-trimester screening protocol could potentially obviate the false-negative cases from other screening tests. The measurement of nasal bone length in the second trimester seems to provide additional benefits beyond the assessment of the presence or absence of the nasal bone.     

The prenatal diagnosis of Pierre-Robin sequence.

The purpose of this study was to evaluate the spectrum of prenatal sonographic and chromosomal findings, associated anomalies and perinatal and neonatal outcomes in cases with Pierre-Robin sequence. All cases (20) with Pierre Robin sequence, who were born at China Medical College Hospital between 1990 and 1997, were included and analysed in this series. 12 pregnancies (60 per cent) were complicated by polyhydramnios and 9 (45 per cent) were combined with cleft palate. Four cases (20 per cent) with cardiac anomalies were also observed. Two fetuses (10 per cent) had abnormal karyotyping (one trisomy 21, one trisomy 18). All fetuses were delivered at or near term. Male deviation was observed in cases with isolated Pierre-Robin sequence or combined mild anomalies (male female ratio: 13:3). Two neonatal mortalities and three with mental retardation were observed. This investigation provides a basis for counselling patients with fetal micrognathia or neonatal Pierre-Robin sequence. The main prenatal sonographic findings of Pierre-Robin sequence are micrognathia, polyhydramnios and cleft palate. In cases of polyhydramnios, sonographic examination of the facial profile and palate are recommended. After the finding of polyhydramnios, micrognathia, and even cleft palate, clinicians should be aware of the possibility of neonatal Pierre-Robin sequence. Cardiac evaluation and karyotyping is also recommended.     

Sonographic features of trisomy 18 at midpregnancy

OBJECTIVE: To evaluate the sonographic characteristics of the fetuses with trisomy 18 at 16-22 weeks of gestation. METHODS: The subjects were recruited from pregnant women undergoing prenatal sonographic examinations at 16-22 weeks of gestation and subsequently proven to be trisomy 18. The results of ultrasound findings were retrospectively reviewed in 25 cases with chromosomes which were confirmed as trisomy 18. RESULTS: All cases had at least one abnormal sonographic finding. There was only one case that had no structural abnormality, but fetal growth restriction was documented. The common sonographic findings included fetal growth restriction, choroid plexus cysts, cardiac anomalies, clenched hand, omphalocele and cleft lip. Fetal growth restriction was the most common finding demonstrated in nearly half of all cases. Other less common findings were diaphragmatic hernia, abnormal head shape, polyhydramnios, single umbilical artery. CONCLUSION: Nearly all fetuses with trisomy 18 had characteristic sonographic patterns of abnormalities demonstrated at midpregnancy. Detailed ultrasound at midpregnancy could effectively screen fetuses with trisomy 18 for further genetic testing.     

Sonographic measurements and ratios in fetuses with Down syndrome

Ultrasound measurements of 15 fetuses with trisomy 21 detected during the 17th week of gestation were matched retrospectively to those of 45 normal controls. We compared nine standard ultrasound measurements of the fetal head, abdomen, and femur in these two groups. The fetuses with trisomy 21 had significantly shorter mean femur lengths, narrower occipitofrontal diameters, and increased biparietal diameter (BPD)/femur length and abdominal circumference/femur length ratios. An increased BPD/femur length ratio was the ultrasound finding that best predicted a fetus with Down syndrome. A BPD/femur length ratio of 1.80 or higher was 40% sensitive and 97.8% specific in predicting Down syndrome, and had a false-positive rate of only 2.2%. An increased second-trimester BPD/femur length ratio measured by ultrasound may prove beneficial as an additional screening test for Down syndrome.     

Echographic measuring of the length of the fetal femur in the screening for Down syndrome]

OBJECTIVE--Our purpose was to assess the value of sonographic measurement of fetal femur length in the second trimester, as a screening tool for Down's syndrome. STUDY DESIGN--We evaluated a consecutive series of fetuses scanned by a single sonologist at the time of amniocentesis between 15 and 19 weeks. The study group consisted of fetuses with Down's syndrome (N = 16); the control group comprised normal fetuses (N = 1163). A linear regression model of the normal femur length based on biparietal diameter (BPD), was established for our population; the ratios of measured to expected femur length for a viven BPD (FL M/E) were calculated in the two groups. To test statistical significance of observed differences between case and control population, unpaired t test was used. The ability of specific FL M/E cut-off values to discriminate between Down syndrome and normal fetuses was assessed by Fisher's exact test. RESULTS--The mean ratio of measured to expected femur length was significantly lower in the Down syndrome as compared with control population (0.9473, DS 0.0795) versus 1.0, DS 0.0745) (p < 0.0045). The ratio of 0.91 or less predicted Down's syndrome with a sensitivity of 43.7% and a false-positive rate of 8.6%. For women with risk of one in 250 and one in 1000 of having an affected fetus based on maternal age, a shortened femur yielded positive predictive values of one in 26 and one in 105, respectively. CONCLUSION--These results suggest that the sonographic measurement of fetal femur length for the screening of Down syndrome in the low-risk population is hindered by a high false positive rate (about 9%). It follows that the percentage of women requiring an amniocentesis would increase to un unacceptably high level. The utilization of this biometric marker may be helpful, in our opinion, for identifying fetuses at risk for Down syndrome in women between 35 and 38 years of age. These women in fact, are not offered amniocentesis for the prenatal diagnosis of Down's syndrome in the majority of italian institutions. The sonographic measurement of fetal femur length could detect about 45% of fetal Down's syndrome, offering an amniocentesis to 9% of women, with a consequent reduction of the cost required. Only a prospective study can evaluate the efficacy of this method to predict Down syndrome in such group of women.     

Femur length shortening in the detection of Down syndrome: is prenatal screening feasible?

The potential utility of screening for femur length shortening in prenatal detection of Down syndrome (trisomy 21) was evaluated by comparing 49 consecutive fetuses with Down syndrome with 572 chromosomally normal fetuses before genetic amniocentesis. Ratios of measured femur length/predicted femur length and biparietal diameter/femur length were calculated for each fetus. The predicted femur length was calculated from a regression equation relating the biparietal diameter and femur length derived from a sample control group. With this normal regression equation, 7 of 49 (14.3%) fetuses with Down syndrome had short femur lengths (measured femur length/predicted femur length ratio of less than or equal to 0.91) compared with 35 of 572 (6.1%) fetuses with a normal karyotype (p less than 0.05). However, the maximum positive predictive value for identification of Down syndrome based on short femur lengths was only 0.93% for a high-risk population (prevalence of Down syndrome, 1:250) and 0.33% for a low-risk population (prevalence of Down syndrome, 1:700). We conclude that ultrasonographic screening of short femur length is less effective for prenatal detection of Down syndrome than initially suggested.     

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.     

Incidence of Chromosomopathies and Cystic Fibrosis Mutations in Second Trimester Fetuses with Isolated Hyperechoic Bowel

Objective: Fetal echoic bowel can be a normal second trimester ultrasonographic finding which usually disappears by 20 weeks on serial sonograms. Recent studies have suggested a possible association of hyperechoic fetal bowel with chromosomopathies and cystic fibrosis. The aim of our study is to determine the incidence of chromosomopathies and cystic fibrosis mutations among the fetuses with isolated hyperechoic bowel.

Methods: Sixteen fetuses with isolated echoic bowel were detected: 13 fetuses S20 weeks gestation (group I) and 3 fetuses at 20-26 weeks gestation (group II). Cytogenetic studies were performed in all 16 cases and 11 families had deoxyribonucleic acid-based risk assessment for cystic fibrosis. The echogenity of bowel was that of surrounding bone.

Results: Two cases of trisomy 21 and 1 case of trisomy 13 were detected (18.7%). The other ultrasonographic markers begin to appear after 21 weeks gestation in fetuses with trisomy 13. Two of 3 pregnant women with pathological karyotype were younger than 35 years. One of 11 cases (9%) was found to be a heterozygote carrier for ΔF508 mutation.

Conclusions: Isolated hyperechoic bowel in the second trimester was found to be associated with a significantly higher risk of fetal aneuploidy.     

Hypoechoic liver in fetuses with trisomy 21

The association between hypoechoic hepatomegaly in the third trimester and transient abnormal myelopoiesis (TAM) was reported previously in six fetuses with trisomy 21 (T21). We report a series of three cases of T21 in which hypoechoic liver (HL) was found in the second trimester but without evidence of TAM on both hematological and histological examination. We postulate that the hypo-echogenicity may be due to liver congestion secondary to hemodynamic disturbances seen in T21 fetuses. All three cases had negative first trimester Down syndrome screening and one case was detected solely because of the isolated finding of HL. HL per se may be associated with T21 and more positive cases are required to support this association.     

Linear insertion of atrioventricular valves without septal defect: a new anatomical landmark for Down's syndrome?

Our objective was to explore whether minor anatomical abnormalities of the septal insertion of tricuspid and mitral valves could be a feature of trisomy 21 in fetuses with an otherwise normal heart. Postmortem examinations were performed in 41 fetuses affected by Down's syndrome and in 52 controls. Adjoining the standard postmortem procedure, an apex-to-base section of the crux of the heart was made on a plane corresponding to the sonographic four-chamber view. This allowed gross and histological examination of the hinge points of tricuspid and mitral leaflets, showing the usual apical displacement of the tricuspid valve in all controls. Of 41 fetuses affected by Down's syndrome, 18 had a structural heart defect. Of the 23 Down syndrome fetuses without a patent heart defect, 16 (i.e., 69% of those considered as having 'normal hearts') had nevertheless a linear insertion of atrioventricular valves at autopsy. Prospective clinical studies are required to evaluate if these postmortem findings can be transposed to the clinical setting of 2nd-trimester sonographic screening.     

Choroid plexus cysts: Is biochemical testing a valuable adjunct to targeted ultrasonography?

OBJECTIVE: We sought to determine whether biochemical testing is a valuable adjunct to ultrasonography in selecting patients with fetal choroid plexus cysts for amniocentesis. STUDY DESIGN: The study population consists of 128 patients who had fetal choroid plexus cysts detected during ultrasonography performed between 18 and 22 weeks' gestation. The patients had genetic counseling, and amniocentesis and biochemical testing were offered to all patients. The data were analyzed by dividing the patients into 3 groups. Group 1 had targeted ultrasonography only, group 2 had ultrasonography and maternal serum alpha-fetoprotein testing, and group 3 had ultrasonography and triple-screen (maternal serum alpha-fetoprotein, human chorionic gonadotropin, and estriol) testing. Outcome was determined by fetal karyotype or by neonatal examination by a pediatrician for patients who declined amniocentesis. RESULTS: There were 25 patients in group 1. Isolated choroid plexus cysts were detected in 20 fetuses, and all had normal outcomes. Additional anomalies were detected in 5 fetuses. Two had normal karyotypes, and 3 had trisomy 18. There were 52 patients in group 2. The maternal serum alpha-fetoprotein levels were normal in 44 patients, 41 of whom had isolated fetal choroid plexus cysts. Of these 44 patients, 40 had normal outcomes, and 1 patient had a fetus with trisomy 18. The remaining 3 patients with normal maternal serum alpha-fetoprotein levels had additional fetal anomalies on ultrasonography, but the karyotypes were normal. The maternal serum alpha-fetoprotein levels were abnormal in 8 patients, of whom 6 had fetuses with isolated choroid plexus cysts and normal karyotypes. Two patients had additional fetal anomalies detected on ultrasonography and had abnormal karyotypes, 1 with trisomy 21 and 1 with trisomy 18. There were 51 patients in group 3. Results of the triple screen were normal in 32 patients. The choroid plexus cysts were isolated in 29 of the 32 patients, and all 29 fetuses had normal karyotypes. The other 3 patients with normal triple-screen results had additional fetal anomalies on ultrasonography. One fetus had normal chromosomes, and 2 had trisomy 18. The remaining 19 patients had abnormal triple-screen results. Among them, 16 fetuses had isolated choroid plexus cysts, 13 of whom were normal, 2 had trisomy 18, and 2 had a de novo unbalanced translocation. The remaining 3 fetuses had additional anomalies, and all 3 fetuses had trisomy 18. There were 14 fetuses with significant chromosomal abnormalities. Nine mothers were <35 years old, and 5 were >/=35 years old. CONCLUSIONS: This study shows the following: (1) The triple screen is a useful adjunct to targeted ultrasonography in selecting patients with fetal choroid plexus cysts for amniocentesis. (2) A normal triple-screen result and the absence of additional fetal anomalies on ultrasonography reliably exclude an underlying chromosomal abnormality, and amniocentesis is not indicated. (3) If the triple-screen result is abnormal, additional anomalies are seen on ultrasonography, or the mother is aged >/=35 years, then fetal karyotyping is recommended. (4) Patients who decline fetal karyotyping should have follow-up ultrasonography in 34 weeks' time.