0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review |

Second-Trimester Ultrasound to Detect Fetuses With Down Syndrome:  A Meta-analysis FREE

Rebecca Smith-Bindman, MD; Wylie Hosmer, BS; Vickie A. Feldstein, MD; Jonathan J. Deeks, MSc; James D. Goldberg, MD
[+] Author Affiliations

Author Affiliations: Departments of Radiology (Drs Smith-Bindman and Feldstein and Mr Hosmer) and Epidemiology and Biostatistics (Dr Smith-Bindman), University of California, San Francisco; ICRF/NHS Centre for Statistics in Medicine, Institute of Health Sciences, University of Oxford, Oxford, England (Mr Deeks); and California Pacific Medical Center, San Francisco (Dr Goldberg).


JAMA. 2001;285(8):1044-1055. doi:10.1001/jama.285.8.1044.
Text Size: A A A
Published online

Context Second-trimester prenatal ultrasound is widely used in an attempt to detect Down syndrome in fetuses, but the accuracy of this method is unknown.

Objective To determine the accuracy of second-trimester ultrasound in detecting Down syndrome in fetuses.

Data Sources English-language articles published between 1980 and February 1999 identified through MEDLINE and manual searches.

Study Selection Studies were included if they recorded second-trimester findings of ultrasonographic markers, chromosomal abnormalities, and clinical outcomes for a well-described sample of women. A total of 56 articles describing 1930 fetuses with Down syndrome and 130 365 unaffected fetuses were included.

Data Extraction Articles were independently reviewed, selected, and abstracted by 2 reviewers. Discrepancies in data abstraction were resolved by consensus with a third reviewer. Overall estimates of sensitivity, specificity, and positive and negative likelihood ratios were calculated for the following markers: choroid plexus cyst, thickened nuchal fold, echogenic intracardiac focus, echogenic bowel, renal pyelectasis, and humeral and femoral shortening. Results were stratified by whether markers were identified in isolation or in conjunction with fetal structural malformations.

Data Synthesis When ultrasonographic markers were observed without associated fetal structural malformations, sensitivity for each was low (range, 1%-16%), and most fetuses with such markers had normal outcomes. A thickened nuchal fold was the most accurate marker for discriminating between unaffected and affected fetuses and was associated with an approximately 17-fold increased risk of Down syndrome. If a thickened nuchal fold is used to screen for Down syndrome, 15 893 average-risk women or 6818 high-risk women would need to be screened for each case of Down syndrome identified. For each of the other 6 markers, when observed without associated structural malformations, the marker had marginal impact on the risk of Down syndrome. Because the markers were detected in only a small number of affected fetuses, the likelihood of Down syndrome did not decrease substantially after normal examination findings (none of the negative likelihood ratios were significant).

Conclusions A thickened nuchal fold in the second trimester may be useful in distinguishing unaffected fetuses from those with Down syndrome, but the overall sensitivity of this finding is too low for it to be a practical screening test for Down syndrome. When observed without associated structural malformations, the remaining ultrasonographic markers could not discriminate well between unaffected fetuses and those with Down syndrome. Using these markers as a basis for deciding to offer amniocentesis will result in more fetal losses than cases of Down syndrome detected, and will lead to a decrease in the prenatal detection of fetuses with Down syndrome.

Figures in this Article

Chromosomal abnormalities occur in 0.1% to 0.2% of live births,14 and the most common clinically significant chromosomal abnormality among liveborn infants is Down syndrome (trisomy 21). Aside from mental retardation, infants with Down syndrome are at high risk of having associated structural defects, including congenital heart disease, craniofacial abnormalities, and gastrointestinal abnormalities.5 Having a child with Down syndrome can be traumatizing and disruptive to families, and the financial burden, including health care expenditures, physical therapy, and special education, can be substantial.6,7 There has been a growing interest in the prenatal detection of affected fetuses so that parents can be prepared for the birth of an affected child or consider pregnancy termination.

The incidence of Down syndrome increases with maternal age,1,8 and until 1984, advanced maternal age was the only factor usually considered to identify those at sufficiently high enough risk to justify amniocentesis and fetal karyotyping. Subsequently, the levels of 4 maternal serum biochemical markers in the second trimester of pregnancy—alpha fetoprotein, human chorionic gonadotropin, estriol, and inhibin A—have been found to be associated with Down syndrome.911 Second-trimester maternal biochemical serum screening for abnormal levels of some or all of these markers is now part of routine obstetrical care in the United States and allows the detection of approximately 60% of cases of Down syndrome, with a false-positive rate of 7%.1214 Since there is considerable overlap of maternal serum values for unaffected and chromosomally abnormal fetuses, a positive screening test result needs to be followed by a diagnostic test. Amniocentesis can reliably determine fetal karyotype, but there is a 0.5% to 1.0% fetal mortality rate associated with this procedure.1520

Most pregnant women undergo prenatal ultrasound during the second trimester as a routine part of antenatal care, and the majority are not at elevated risk of having a fetus with Down syndrome based on age or serum testing results. A high percentage of chromosomally abnormal fetuses have structural abnormalities that might be recognized on prenatal ultrasound, although these have typically been difficult to detect.2140 Several sonographic "markers" have also been reported to be associated with chromosomal abnormalities, including choroid plexus cysts and nuchal fold thickening. While not pathologic themselves, these markers have been used to screen for or adjust the risk for Down syndrome.4147 Two previous quantitative summaries of second-trimester ultrasound for the detection of Down syndrome have been published48,49; however, both pooled the results of all studies despite profoundly inconsistent results, and neither study stratified the results by whether the markers were seen in conjunction with fetal structural abnormalities. Thus, the true accuracy of the markers is unknown.

While ultrasound has potential to improve the performance of a Down syndrome screening program, it can also cause harm by prompting unnecessary medical intervention, anxiety related to false-positive findings, and false reassurance to women with affected pregnancies who may be dissuaded from undergoing a diagnostic test because of a normal ultrasound result.49,50 We reviewed the literature and used meta-analytic techniques to estimate the accuracy of prenatal ultrasound in screening for Down syndrome.

Data Sources

We performed a MEDLINE search for articles published between January 1980 and February 1999 and manually searched bibliographies of relevant published articles. The MEDLINE search included the following second-trimester ultrasonographic markers that have been reported to be associated with chromosomal abnormalities: choroid plexus cyst, nuchal fold thickening, echogenic intracardiac focus, echogenic bowel, renal pyelectasis, shortened humerus, shortened femur, and fetal structural malformations. Additional MEDLINE search terms included Down syndrome, trisomy 21, prenatal ultrasound, chromosomal abnormality, diagnostic tests, biochemical testing, and genetic ultrasound. Review articles, letters, case reports, comments, and non–English-language articles were excluded.

Study Selection

Articles were independently selected and reviewed, and their data were extracted by 2 investigators. Studies were included that recorded second-trimester prenatal ultrasonographic markers and outcome information on a well-described sample of women, and from which estimates of sensitivity and specificity could be calculated (n = 220). Retrospective studies were included provided that the original ultrasound interpretation was used. Active ascertainment of all pregnancy outcomes by chromosomal analysis or visual inspection was required for study inclusion. Studies were excluded if they reported fewer than 5 fetuses with a chromosomal abnormality (n = 15); obtained outcome data only on fetuses with a specific ultrasound finding (n = 68); had incomplete follow-up (n = 11); performed the ultrasound following genetic testing (n = 7); or were primarily focused on a different topic (eg, only looked at major structural abnormalities or had no information on clinical outcomes) (n = 45). Studies that were based on first-trimester ultrasound were not included (n = 18). When relevant data could not be extracted from published articles, the corresponding author was contacted to obtain additional information (n = 5, 1 of whom responded.) For studies that resulted in multiple publications, data from the most recent publication were used. A full list of excluded studies is available from the authors with reasons for their exclusion.

Data Abstraction

Data were abstracted for each of the following ultrasonographic markers: choroid plexus cyst, nuchal fold thickening, echogenic intracardiac focus, echogenic bowel, renal pyelectasis, shortened humerus, shortened femur, and fetal structural malformations. Data are not presented for the following: shortened ear length, shortened middle phalanx, sandal gap deformity, and increased iliac angle (other markers of Down syndrome), because fewer than 5 articles were found for each and most did not meet the inclusion criteria. The types of fetal structural abnormalities were recorded by organ system (central nervous system, neck, heart, lung, intestine, renal, face, other, and unspecified) and included a range of malformations.

For each article, 2 of the authors abstracted and recorded the number of true-positive, false-positive, true-negative, and false-negative results for each of the markers. Whenever possible, data were abstracted separately for the markers seen as an isolated abnormality or in combination with fetal structural malformations. The following definitions of the markers were used: choroid plexus cysts, cysts of any size or number in the cerebral ventricles (Figure 1A); nuchal fold thickening, thickness of 6 mm or greater (Figure 1B); echogenic intracardiac focus, punctate intracardiac echogenic focus within either ventricle (Figure 1C); renal pyelectasis, anterior-posterior diameter of the renal pelvis of 4 mm or greater (Figure 1D); and echogenic bowel, echogenicity (brightness) equal to or greater than bone (Figure 1E). Data were abstracted for more than 90% of the studies using these definitions. Femur and humerus shortening were less consistently defined (not shown). They were most often defined as an observed-to-expected length ratio of less than 0.90, and the expected length was based on the biparietal diameter using an equation generated from a normal population. Seven of the 11 humerus and 19 of the 29 femur studies used these definitions. In 8 of the femur studies, the definition of a shortened femur was a ratio of biparietal diameter to femur length of greater than 1.5 SDs from the mean for the normal population.

Figure 1. Fetal Ultrasonographic Markers for Risk of Down Syndrome
Graphic Jump Location
A, Fetal brain with a choroid plexus cyst. B, Fetal neck demonstrating thickening of the nuchal region. C, Bright focus in the fetal heart (echogenic intracardiac focus). D, Dilation of the renal collecting systems (renal pyelectasis). E, Increased brightness in the fetal bowel (echogenic bowel). Humeral and femoral shortening are defined by comparing measurements to a normal distribution and are not illustrated.

Because some of the abnormal ultrasound findings have been described in association with other chromosomal anomalies as well as Down syndrome, 3 fetal outcomes were considered: unaffected, Down syndrome, or all chromosomal abnormalities when data for Down syndrome alone were unavailable. All chromosomal abnormalities was the outcome used in 50% of the articles relating to the finding of choroid plexus cyst. For the other ultrasonographic markers, we were able to abstract data specifically for Down syndrome from the vast majority of articles.

For each article, the study date, maternal risk of chromosomal abnormality, and the presence and type of structural abnormalities were recorded. Discrepancies in data abstraction between investigators were resolved by reaching a consensus with a third author.

Data Synthesis

For each study, the sensitivity, specificity, and exact 95% confidence intervals (CIs) were calculated for each of the ultrasound findings. Although we used narrow definitions for each of the markers, studies may have used varying implicit definitions for an abnormal result.51 Before we combined the results across studies, we sought evidence of a trade-off between sensitivity and specificity introduced through varying thresholds by testing for a correlation between true-positive and false-positive rates.52 Such a trade-off would argue against the appropriateness of summarizing the accuracy measures as single point estimates, favoring the use of more complex summary receiver operating characteristic curve analysis.

Pooled estimates of sensitivity and specificity were calculated for each ultrasound finding using a single-term logistic regression model, and the unit of analysis was the study. This method produces results similar to those obtained from calculating a weighted average of the sensitivities and specificities, weighting by sample size. The consistency of the study results was assessed by considering the "goodness-of-fit" deviance statistic. The dispersion of the data was calculated by dividing the deviance statistic by its df: dispersions >1 correspond to variability greater than that expected by chance. Where the fit was poor, the model was adjusted to account for the overdispersion by multiplying the SE by the square root of the dispersion statistic.

The sensitivity and specificity estimates were calculated stratified by whether the finding was seen as an isolated abnormality or in conjunction with other structural abnormalities. When studies did not explicitly state either, they were labeled as unknown and analyzed separately. Results were also stratified by study design and size. To identify whether the results might be influenced by study design, sample size, or by whether the markers were reported in isolation, terms for these factors were introduced into the logistic regression model.

Positive and negative likelihood ratios (LRs) were calculated for each ultrasound finding, stratified by whether it was seen in isolation or in association with fetal structural malformations, and were pooled using a DerSimonian and Laird random effects method for pooling risk ratios.53 All analyses were performed with STATA statistical software (release 6.0, STATA Corp, College Station, Tex).

Positive and negative predictive values were calculated at a disease prevalence of 1:700 (the population prevalence of Down syndrome) and 1:300 (equivalent to the mid second-trimester prevalence in a 35-year-old woman and generally considered high-risk for Down syndrome) by application of Bayes theorem to the estimated LRs. For each ultrasound finding, the number of women that would need to be screened to detect a case of Down syndrome was calculated as the inverse of the product of the prevalence of Down syndrome and the sensitivity of the ultrasound finding. The number of normal fetuses that would be lost for each case of Down syndrome identified was calculated assuming that all screen-positive ultrasound examinations were followed by invasive diagnostic testing, and that the rate of fetal loss per amniocentesis procedure is 0.8%.1620

Fifty-six studies met inclusion criteria and described 130 365 unaffected fetuses and 1930 cases of Down syndrome (Table 1).22,26,27,38,4046,5498 The mean maternal age was 34 years, and 88% of the studies (n = 49) included women at increased risk of chromosomal abnormality based on age (n = 39), serum biochemical testing (n = 36), or family history of chromosomal abnormality (n = 16). The number of women who were at increased risk for each indication was generally not provided. The overall prevalence of Down syndrome was 1.5% (compared with 0.1% in the general population). Down syndrome was present in 6% of the women in case-control studies (n = 24) compared with 1% in the prospective studies. Outcome ascertainment included fetal karyotyping in 53 studies (95%). The number of studies that evaluated each marker ranged from 5 to 29. For studies that included fetal structural malformations, the types of abnormalities specified varied widely, ranging from mild, such as cleft lip, to lethal, such as anencephaly.

Table Graphic Jump LocationTable 1. Description of Included Studies*
Sensitivity and Specificity

The sensitivity and 1 − specificity (false-positive rate) reported by each study for the ability to detect cases of Down syndrome are presented for each ultrasonographic marker in Figure 2. The results were markedly heterogeneous for all findings. For example, the percentage of fetuses with Down syndrome correctly identified using a thickened nuchal fold varied from 7%63 to 75%.41,68 These reported differences in detection were not the result of a trade-off between the sensitivity and specificity (Spearman correlations between the sensitivity and the specificity were not significant, and there is no obvious trend in the false-positive rates in Figure 2 when ordered by the sensitivity rates).

Figure 2. Sensitivity and False-Positive Rates (1 − Specificity)
Graphic Jump Location
Data shown for all studies that examined the ultrasonographic markers as screening tests for Down syndrome. One summary estimate is included for each study. The category of "composite findings" was defined differently by each study, but in general included some or all of the markers, in addition to structural abnormalities. Error bars indicate 95% confidence intervals.

We explored possible reasons for the inconsistency across studies, illustrated for nuchal fold in Table 2. There were no differences in the sensitivity based on study size (test for difference between groups, P = .23). However, we found significant differences in the reported accuracy based on study design (test for difference, P = .008) and whether the marker was seen as an isolated abnormality or in association with fetal structural abnormalities (test for difference, P<.001).

Table Graphic Jump LocationTable 2. Investigation of Reasons for Heterogeneity of Studies Examining Nuchal Fold Thickening as a Marker for Down Syndrome (n = 26)

The sensitivity was significantly lower among studies that reported the results of the markers as isolated abnormalities, illustrated for thickened nuchal fold in Figure 3. For example, a thickened nuchal fold observed in isolation was seen in 4% of cases of Down syndrome, compared with 26% when observed in addition to other abnormalities. Additionally, the results were more consistent among the studies that reported on the isolated findings: most of the CIs for these studies overlap the summary estimate (Figure 3).99

Figure 3. Sensitivity for All Studies That Examined Nuchal Fold Thickening
Graphic Jump Location
Data shown for all studies using nuchal fold thickening as a screening test for Down syndrome. Studies are stratified by whether the nuchal fold was evaluated as an isolated abnormality, was seen in conjunction with other abnormalities, or the study did not report whether the nuchal fold was seen as an isolated abnormality (unknown). For studies in which data could be abstracted for both an isolated nuchal fold and for a nuchal fold seen in addition to other abnormalities, 2 data points are included. Size of data markers reflects study sample size; dotted line reflects the point estimates for pooled data.

For each of the ultrasonographic markers, the sensitivity for Down syndrome was low when the marker was seen without associated structural malformations or other markers, ranging from 1% for choroid plexus cyst (95% CI, 0%-3%) to 16% for shortened femur (95% CI, 5%-40%) (Table 3). The specificity for each of the markers was greater than 95% when the finding was seen as an isolated abnormality.

Table Graphic Jump LocationTable 3. Summary Sensitivity and Specificity for Each Ultrasonographic Marker*
Positive and Negative LRs

If nuchal fold thickening is identified in the second trimester, the odds of Down syndrome increase by approximately 17-fold (positive LR, 17; 95% CI, 8-38) (Table 4). For the other 6 markers, the positive LRs were significantly lower, and for choroid plexus cyst and renal pyelectasis, the positive LRs were not significant. Because the markers were seen in only a minority of abnormal fetuses, a normal finding did not substantially decrease the risk of a fetus having Down syndrome. None of the negative LRs were significant.

Table Graphic Jump LocationTable 4. Summary Accuracy Measures for Each Ultrasonographic Marker When Identified as an Isolated Abnormality*
Positive and Negative Predictive Values

Among women at average risk of having a fetus with Down syndrome, if a thickened nuchal fold is identified, the risk is 2% (Table 4), and among women at high risk, the risk is 5%. The positive predictive values were significantly lower for the 6 other markers (≤1% in low-risk women, and ≤2% in high-risk women for each of the markers). The negative predictive value for each of the markers was greater than 99%, reflecting the rarity of Down syndrome.

Number Needed to Screen

If ultrasound screening is used in women who are at average risk of having an affected fetus, the number needed to be screened to detect a case of Down syndrome is high (range, 4454-87 413) depending on the marker used (Table 4). For each case of Down syndrome correctly identified, there will be false-positive diagnoses, ranging from 79 (for nuchal fold) to 611 (for choroid plexus cysts). Because an abnormal finding is followed by amniocentesis to make a definitive diagnosis, there will be inevitable losses of unaffected fetuses as a complication of amniocentesis. For example, if the presence of an echogenic intracardiac focus is used as a basis to offer amniocentesis, 2 fetal losses in low-risk women and 1 fetal loss in high-risk women will occur as complications for each case of Down syndrome identified.

Sensitivity Analysis

One study contributed approximately 25% of the unaffected fetuses to our meta-analysis (n = 33 000).63 To determine the impact of this study on the overall summary measures, the sensitivity and specificity rates were recalculated excluding that study's data, and there was no change in the sensitivity rates for any of the markers. On the other hand, the false-positive rates doubled when this study was deleted (for choroid plexus cyst, the false-positive rate increased from 1% to 3%, for nuchal fold from 0.5% to 0.9%, and for echogenic bowel from 1% to 3%). Within the studies that considered isolated markers, there was typically no evidence of a trade-off between the true-positive and false-positive rates (eg, for nuchal fold the correlation between sensitivity and specificity was not significant [P = .27]), and thus summary statistics could be calculated and are valid.

When seen as isolated findings, the second-trimester ultrasonographic markers of choroid plexus cyst, echogenic intracardiac focus, echogenic bowel, renal pyelectasis, shortened humerus, and shortened femur are not helpful in either confirming or excluding the presence of Down syndrome.100 Only 1 marker, thickened nuchal fold, may be useful at distinguishing between unaffected and affected fetuses. If nuchal fold thickening is identified, the risk of Down syndrome increases by approximately 17-fold. However, this marker is present in only a minority of fetuses with Down syndrome, and many fetuses would need to be screened for nuchal fold thickening to make a single diagnosis of Down syndrome.

Moreover, because the sensitivity of the ultrasonographic markers is so low, and because Down syndrome is rare, the vast majority (>99%) of fetuses with an isolated marker will be unaffected. The use of the ultrasonographic markers as an indicator for invasive testing with amniocentesis will lead to an increase in the number of unaffected fetuses lost as a complication of the procedure. Although women may place different values on the balance between the identification of a fetus with Down syndrome and the loss of an unaffected fetus due to a complication of amniocentesis,101 this highlights an important potential harm associated with a test often considered risk-free. If, for example, identification of an echogenic intracardiac focus is used as a basis for offering amniocentesis to pregnant women at low risk of carrying an affected fetus, 2 unaffected fetuses will be lost as a complication of amniocentesis for each correctly identified Down syndrome case. Additionally, because the false-positive rate is 1% or greater for most of the markers, when all of these markers are used in aggregate, the false-positive rate may approach 10% or more, leading to much needless anxiety throughout pregnancy and beyond.50,102104

Furthermore, if women who are at elevated risk of carrying a fetus with Down syndrome based on maternal age or serum testing results are dissuaded from amniocentesis due to the absence of ultrasonographic markers, this will reduce the prenatal detection of fetuses with Down syndrome as well as the effectiveness of biochemical screening.49 Finally, there are significant costs associated with ultrasound screening for Down syndrome, particularly those that relate to the further evaluation of detected findings. Even for nuchal fold thickening, more than 15 000 scans would need to be performed in average-risk women and more than 6000 scans in high-risk women to detect a single case of Down syndrome. Based on available data, the accuracy of a second-trimester ultrasound screening program would be far less, and the cost far greater, than that achieved by current biochemical screening.105 There are no data on whether serum markers and these ultrasonographic markers are independent indicators of Down syndrome risk, and thus it is unclear whether the use of the ultrasonographic markers contributes any additional detection to that achievable with serum testing.

Although our results suggest poor accuracy for most of these ultrasonographic markers, it is common practice for clinicians to use them as evidence of an increased risk of Down syndrome.50,106 For example, in a large health maintenance organization in California, all pregnant women are offered second-trimester ultrasound to screen for fetal anomalies. If a choroid plexus cyst is identified, the patient literature reports that the fetus has a 1:100 risk of chromosomal abnormality and the woman may undergo amniocentesis. This is 7-fold her a priori risk of chromosomal abnormality, and this increased risk is not supported by our results. Similarly, Boyd et al63 found that while the presence of ultrasonographic markers increased the prenatal detection of malformed fetuses by only 4%, identification of the markers was responsible for a 12-fold increase in the false-positive rate.

Although our review cannot exclude the possibility that there is benefit to identifying these markers, their validity is not supported by our findings. Furthermore, although we focused on the most common ultrasonographic markers used to screen for chromosomal abnormalities, there are many others described in the literature and evaluated in even fewer patients.

Our meta-analysis focused on the ultrasonographic markers that may be seen in isolation. Many of the studies examined these markers in conjunction with other markers and with fetal structural abnormalities. Using such a combination may improve the accuracy of screening with ultrasound. However, these studies reported statistically inconsistent results, and thus a summary measure of the accuracy of a composite score could not be determined. Furthermore, the low sensitivity of the isolated markers suggests that these may not contribute to the information provided by the presence of fetal structural malformations. Our analysis suggests that the high sensitivity for Down syndrome reported by many studies using ultrasonographic markers may be due to the detection of the associated structural abnormalities. None of the negative LRs were significant; thus, the absence of an individual marker could not be used to rule out Down syndrome. Therefore, it seems improbable that the absence of a combination of ultrasonographic markers would substantially decrease the risk of Down syndrome.

It is important to distinguish between the ultrasonographic markers, which are themselves harmless, and fetal structural abnormalities for several reasons. First, the prenatal identification of fetal structural malformations may have benefit to the mother unrelated to the risk of chromosomal abnormality (eg, the family can anticipate the special needs of the child).50 Second, most clinicians believe that detection of a major structural abnormality is sufficient grounds to offer invasive testing. Finally, the vast majority of examinations demonstrating isolated sonographic markers are false-positives.

We focused on second-trimester ultrasound and did not include studies of nuchal translucency screening, a first-trimester ultrasound test used at approximately 10 to 14 weeks' gestation. Currently, this test has not been embraced into clinical practice in the United States, the implications of the accuracy of this test on clinical management are far different than for markers observed on routine ultrasound at 15 to 24 weeks' gestation, and prospective studies of nuchal translucency screening are under way.

Our analysis has several limitations. We may have missed unpublished work, particularly of smaller studies, but these are unlikely to substantially affect the results. Broadening the search to include other electronic databases and articles in languages other than English may have increased the number of studies included, but it seems unlikely that it would make our results any more favorable toward ultrasound. The results may predominantly reflect the findings of specialized centers, and this may inflate the accuracy in a general community setting. The majority of included studies were confined to high-risk pregnancies, such as women referred for prenatal diagnosis because of advanced maternal age or a positive serum screening test result, and the sensitivity of the markers may be different, and probably lower, in low-risk women.

We excluded many studies on the basis of methodologic criteria. It was not possible to determine if including these studies would have had a significant impact on the overall results because most of these excluded studies (n = 67) reported only a positive predictive value, without reporting the risk of Down syndrome among the population studied or the false-positive rate of the marker. The exclusion of the study that contributed 25% of the unaffected fetuses to this meta-analysis resulted in considerably lower estimates of the sensitivity, and worse estimates of screening performance of choroid plexus cyst, nuchal fold, and echogenic bowel.63 That study collected results from an anomaly registry, and it is not clear if all of the cases with sonographic markers had been reported. In addition, we pooled the results from studies that used different designs, including case-control studies, which are likely to lead to overestimation of the sensitivity,107 so that the true accuracy of these findings may be even lower than we report.

In summary, we found that a thickened nuchal fold may be useful in distinguishing between unaffected fetuses and those with Down syndrome, but that the overall sensitivity of this finding is low, and thus it is not practical for use as a screening test. The remaining ultrasonographic markers did not discern well between unaffected fetuses and those with Down syndrome. Because the use of these markers may be associated with more harm than benefit, clinicians should be very cautious about the use of these markers to counsel women about their risk of having a fetus with Down syndrome.

Adams MM, Erickson JD, Layde PM, Oakley GP. Down's syndrome: recent trends in the United States.  JAMA.1981;246:758-760.
Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants.  JAMA.1983;249:2034-2038.
Norton ME. Biochemical and ultrasound screening for chromosomal abnormalities.  Semin Perinatol.1994;18:256-265.
 The California Expanded AFP Screening Program: Prenatal Care Provider Handbook . California Dept of Health Services, Genetic Disease Branch; 1997.
Jones K. Smith's Recognizable Patterns of Human Malformation. 4th ed. Philadelphia, Pa: WB Saunders; 1988.
Waitzman NJ, Romano PS, Scheffler RM. Estimates of the economic costs of birth defects.  Inquiry.1994;31:188-205.
Oberfield RG, Paul H. Prematurity, birth defects, and early death: impact on the family. In: Lewis M, ed. Child and Adolescent Pyschiatry: A Comprehensive Textbook. Baltimore, Md: Williams & Wilkins Co; 1991.
Hook EB, Lindsjö A. Down syndrome in live births by single year maternal age interval in a Swedish study.  Am J Hum Genet.1978;30:19-27.
Canick JA, Knight GJ, Palomaki GE.  et al.  Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome.  Br J Obstet Gynaecol.1988;95:330-333.
Wald NJ, Cuckle HS, Densem JW.  et al.  Maternal serum screening for Down's syndrome in early pregnancy .  BMJ.1988;297:883-887. [published erratum appears in BMJ. 1988;297:1029].
Wald NJ, Cuckle HS, Densem JW.  et al.  Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome.  Br J Obstet Gynaecol.1988;95:334-341.
Palomaki GE, Knight GJ, McCarthy J.  et al.  Maternal serum screening for fetal Down syndrome in the United States: a 1992 survey.  Am J Obstet Gynecol.1993;169:1558-1562.
Haddow JE, Palomaki GE, Knight GJ.  et al.  Prenatal screening for Down's syndrome with use of maternal serum markers.  N Engl J Med.1992;327:588-593.
Haddow JE, Palomaki GE, Knight GJ.  et al.  Second trimester screening for Down's syndrome using maternal serum dimeric inhibin A.  J Med Screen.1998;5:115-119.
The Canadian Early and Mid-trimester Amniocentesis Trial (CEMAT) Group.  Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis.  Lancet.1998;351:242-247.
Tabor A, Philip J, Madsen M.  et al.  Randomised controlled trial of genetic amniocentesis in 4606 low-risk women.  Lancet.1986;1:1287-1293.
Greenough A, Yuksel B, Naik S.  et al.  Invasive antenatal procedures and requirement for neonatal intensive care unit admission.  Eur J Pediatr.1997;156:550-552.
Milner AD, Hoskyns EW, Hopkin IE. The effects of mid-trimester amniocentesis on lung function in the neonatal period.  Eur J Pediatr.1992;151:458-460.
 Midtrimester amniocentesis for prenatal diagnosis: safety and accuracy.  JAMA.1976;236:1471-1476.
 An assessment of the hazards of amniocentesis: report to the Medical Research Council by their Working Party on Amniocentesis  Br J Obstet Gynaecol.1978;85 Suppl 2:1-41.
Nicolaides K, Shawwa L, Brizot M, Snijders R. Ultrasoundally detectable markers of fetal chromosomal defects.  Ultrasound Obstet Gynecol.1993;3:56-59.
Nyberg DA, Resta RG, Luthy DA.  et al.  Prenatal sonographic findings of Down syndrome: review of 94 cases.  Obstet Gynecol.1990;76:370-377.
Stoll C, Alembik Y, Dott B.  et al.  Evaluation of prenatal diagnosis of congenital heart disease.  Prenat Diagn.1993;13:453-461.
Davis GK, Farquhar CM, Allan LD.  et al.  Structural cardiac abnormalities in the fetus.  Br J Obstet Gynaecol.1990;97:27-31.
Halliday J, Lumley J, Bankier A. Karyotype abnormalities in fetuses diagnosed as abnormal on ultrasound before 20 weeks' gestational age.  Prenat Diagn.1994;14:689-697.
Hill LM, Guzick D, Belfar HL.  et al.  The current role of sonography in the detection of Down syndrome.  Obstet Gynecol.1989;74:620-623.
Lynch L, Berkowitz GS, Chitkara U.  et al.  Ultrasound detection of Down syndrome.  Obstet Gynecol.1989;73:267-270.
Meagher S, Renshaw R, Smith A, Milligan J. Chromosomal abnormalities detected after an abnormal ultrasound in pregnancy.  Clin Exp Obstet Gynecol.1994;21:215-220.
Chitty LS. Ultrasound screening for fetal abnormalities.  Prenat Diagn.1995;15:1241-1257.
Chew S, Anandakumar C, Jayanthi V.  et al.  Incidence of chromosomal abnormalities in 153 pregnancies with ultrasound detected fetal abnormalities.  Singapore Med J.1996;37:595-597.
Carlson DE, Platt LD. Ultrasound detection of genetic anomalies.  J Reprod Med.1992;37:419-426.
Bernaschek G, Kolankaya A, Stuempflen I, Deutinger J. Chromosomal abnormalities: how much can we predict by ultrasound examination in low-risk pregnancies?  Am J Perinatol.1996;13:259-263.
Chitty LS, Hunt GH, Moore J, Lobb MO. Effectiveness of routine ultrasound in detecting fetal structural abnormalities in a low risk population.  BMJ.1991;303:1165-1169.
Crane JP, LeFevre ML, Winborn RC.  et al.  A randomized trial of prenatal ultrasound screening.  Am J Obstet Gynecol.1994;171:392-399.
Levi S, Schaaps JP, De Havay P.  et al.  End-result of routine ultrasound screening for congenital anomalies.  Ultrasound Obstet Gynecol.1995;5:366-371.
Luck CA. Value of routine ultrasound scanning at 19 weeks.  BMJ.1992;304:1474-1478.
Shirley IM, Bottomley F, Robinson VP. Routine radiographer screening for fetal abnormalities by ultrasound in an unselected low risk population.  Br J Radiol.1992;65:564-569.
Benacerraf BR, Cnann A, Gelman R.  et al.  Can sonographers reliably identify anatomic features associated with Down syndrome in fetuses?  Radiology.1989;173:377-380.
Benacerraf BR. The second-trimester fetus with Down syndrome.  Ultrasound Obstet Gynecol.1996;7:147-155.
Nyberg DA, Luthy DA, Resta RG.  et al.  Age-adjusted ultrasound risk assessment for fetal Down's syndrome during the second trimester.  Ultrasound Obstet Gynecol.1998;12:8-14.
Benacerraf BR, Gelman R, Frigoletto Jr FD. Sonographic identification of second-trimester fetuses with Down's syndrome.  N Engl J Med.1987;317:1371.
Bromley B, Lieberman E, Laboda L, Benacerraf BR. Echogenic intracardiac focus.  Obstet Gynecol.1995;86:998-1001.
Lockwood C, Benacerraf B, Krinsky A.  et al.  A sonographic screening method for Down syndrome.  Am J Obstet Gynecol.1987;157:803-808.
Nyberg DA, Resta RG, Hickok DE.  et al.  Femur length shortening in the detection of Down syndrome.  Am J Obstet Gynecol.1990;162:1247-1252.
Vintzileos AM, Campbell WA, Guzman ER.  et al.  Second-trimester ultrasound markers for detection of trisomy 21.  Obstet Gynecol.1997;89:941-944.
Nadel AS, Bromley B, Frigoletto Jr 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.
Winter TC, Uhrich SB, Souter VL, Nyberg DA. The "genetic sonogram": comparison of the index scoring system with the age-adjusted US risk assessment.  Radiology.2000;215:775-782.
Vintzileos AM, Egan JF. Adjusting the risk for trisomy 21 on the basis of second-trimester ultrasound.  Am J Obstet Gynecol.1995;172:837-844.
Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down's syndrome.  J Med Screen.1997;4:181-246.
Filly RA. Obstetrical sonography: the best way to terrify a pregnant woman.  J Ultrasound Med.2000;19:1-5.
Irwig L, Macaskill P, Glasziou P, Fahey M. Meta-analytic methods for diagnostic test accuracy.  J Clin Epidemiol.1995;48:119-130.
Deeks JJ. Systematic reviews of evaluations of diagnostic and screening tests. In: Egger M, Smith GD, Altman DG, eds. Systematic Reviews in Health Care: Meta-Analysis in Context. 2nd ed. London, England: BMJ Books; 2001.
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials.1986;7:177-188.
Bahado-Singh RO, Goldstein I, Uerpairojkit B.  et al.  Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results.  Am J Obstet Gynecol.1995;173:1106-1110.
Bahado-Singh RO, Deren O, Tan A.  et al.  Ultrasoundally adjusted midtrimester risk of trisomy 21 and significant chromosomal defects in advanced maternal age.  Am J Obstet Gynecol.1996;175:1563-1568. [published erratum appears in Am J Obstet Gynecol 1997;176:1400].
Benacerraf BR, Barss VA, Laboda LA. A sonographic sign for the detection in the second trimester of the fetus with Down's syndrome.  Am J Obstet Gynecol.1985;151:1078-1079.
Benacerraf BR, Frigoletto Jr FD, Cramer DW. Down syndrome: sonographic sign for diagnosis in the second-trimester fetus.  Radiology.1987;163:811-813.
Benacerraf BR, Neuberg D, Frigoletto Jr FD. Humeral shortening in second-trimester fetuses with Down syndrome.  Obstet Gynecol.1991;77:223-227.
Benacerraf BR, Neuberg D, Bromley B, Frigoletto Jr FD. Sonographic scoring index for prenatal detection of chromosomal abnormalities.  J Ultrasound Med.1992;11:449-458.
Benacerraf BR, Nadel A, Bromley B. Identification of second-trimester fetuses with autosomal trisomy by use of a sonographic scoring index.  Radiology.1994;193:135-140.
Biagiotti R, Periti E, Cariati E. Humerus and femur length in fetuses with Down syndrome.  Prenat Diagn.1994;14:429-434.
Borrell A, Costa D, Martinez JM.  et al.  Criteria for fetal nuchal thickness cut-off.  Prenat Diagn.1997;17:23-29.
Boyd PA, Chamberlain P, Hicks NR. 6-Year experience of prenatal diagnosis in an unselected population in Oxford, UK.  Lancet.1998;352:1577-1581.
Bromley B, Lieberman E, Benacerraf BR. The incorporation of maternal age into the sonographic scoring index for the detection at 14-20 weeks of fetuses with Down's syndrome.  Ultrasound Obstet Gynecol.1997;10:321-324.
Brumfield CG, Hauth JC, Cloud GA.  et al.  Sonographic measurements and ratios in fetuses with Down syndrome.  Obstet Gynecol.1989;73:644-646.
Campbell WA, Vintzileos AM, Rodis JF.  et al.  Efficacy of the biparietal diameter/femur length ratio to detect Down syndrome in patients with an abnormal biochemical screen.  Fetal Diagn Ther.1994;9:175-182.
Chan L, Hixson JL, Laifer SA.  et al.  A sonographic and karyotypic study of second-trimester fetal choroid plexus cysts.  Obstet Gynecol.1989;73:703-706.
Crane JP, Gray DL. Sonographically measured nuchal skinfold thickness as a screening tool for Down syndrome.  Obstet Gynecol.1991;77:533-536.
Cuckle H, Wald N, Quinn J.  et al.  Ultrasound fetal femur length measurement in the screening for Down's syndrome.  Br J Obstet Gynaecol.1989;96:1373-1378.
Deren O, Mahoney MJ, Copel JA, Bahado-Singh RO. Subtle ultrasound anomalies.  Am J Obstet Gynecol.1998;178:441-445.
DeVore GR, Alfi O. The use of color Doppler ultrasound to identify fetuses at increased risk for trisomy 21.  Obstet Gynecol.1995;85:378-386.
Dicke JM, Gray DL, Songster GS, Crane JP. Fetal biometry as a screening tool for the detection of chromosomally abnormal pregnancies.  Obstet Gynecol.1989;74:726-729.
Donnenfeld AE, Carlson DE, Palomaki GE.  et al.  Prospective multicenter study of second-trimester nuchal skinfold thickness in unaffected and Down syndrome pregnancies.  Obstet Gynecol.1994;84:844-847.
D'Ottavio G, Meir YJ, Rustico MA.  et al.  Screening for fetal anomalies by ultrasound at 14 and 21 weeks.  Ultrasound Obstet Gynecol.1997;10:375-380.
Drugan A, Johnson MP, Reichler A.  et al.  Second-trimester minor ultrasound anomalies.  Obstet Gynecol.1996;88:203-206.
Ginsberg N, Cadkin A, Pergament E, Verlinsky Y. Ultrasound detection of the second-trimester fetus with trisomy 18 and trisomy 21.  Am J Obstet Gynecol.1990;163:1186-1190.
Grandjean H, Sarramon MF. Femur/foot length ratio for detection of Down syndrome.  Am J Obstet Gynecol.1995;173:16-19.
Grandjean H, Sarramon MF. Sonographic measurement of nuchal skinfold thickness for detection of Down syndrome in the second-trimester fetus.  Obstet Gynecol.1995;85:103-106.
Gray DL, Winborn RC, Suessen TL, Crane JP. Is genetic amniocentesis warranted when isolated choroid plexus cysts are found?  Prenat Diagn.1996;16:983-990.
Gray DL, Crane JP. Optimal nuchal skin-fold thresholds based on gestational age for prenatal detection of Down syndrome.  Am J Obstet Gynecol.1994;171:1282-1286.
Grist TM, Fuller RW, Albiez KL, Bowie JD. Femur length in the US prediction of trisomy 21 and other chromosomal abnormalities.  Radiology.1990;174:837-839.
Johnson MP, Barr Jr M, Treadwell MC.  et al.  Fetal leg and femur/foot length ratio: a marker for trisomy 21.  Am J Obstet Gynecol.1993;169:557-563.
Johnson MP, Michaelson JE, Barr Jr M.  et al.  Combining humerus and femur length for improved ultrasound identification of pregnancies at increased risk for trisomy 21.  Am J Obstet Gynecol.1995;172:1229-1235.
LaFollette L, Filly RA, Anderson R, Golbus MS. Fetal femur length to detect trisomy 21.  J Ultrasound Med.1989;8:657-660.
Lockwood CJ, Lynch L, Ghidini A.  et al.  The effect of fetal gender on the prediction of Down syndrome by means of maternal serum alpha-fetoprotein and ultrasound parameters.  Am J Obstet Gynecol.1993;169:1190-1197.
Manning JE, Ragavendra N, Sayre J.  et al.  Significance of fetal intracardiac echogenic foci in relation to trisomy 21.  AJR Am J Roentgenol.1998;170:1083-1084.
Marquette GP, Boucher M, Desrochers M, Dallaire L. Screening for trisomy 21 with ultrasound determination of biparietal diameter/femur length ratio.  Am J Obstet Gynecol.1990;163:1604-1605.
Nicolaides KH, Snijders RJ, Gosden CM.  et al.  Ultrasoundally detectable markers of fetal chromosomal abnormalities.  Lancet.1992;340:704-707.
Nyberg DA, Resta RG, Luthy DA.  et al.  Humerus and femur length shortening in the detection of Down's syndrome.  Am J Obstet Gynecol.1993;168:534-538.
Nyberg DA, Luthy DA, Cheng EY.  et al.  Role of prenatal ultrasound in women with positive screen for Down syndrome on the basis of maternal serum markers.  Am J Obstet Gynecol.1995;173:1030-1035.
Rodis JF, Vintzileos AM, Fleming AD.  et al.  Comparison of humerus length with femur length in fetuses with Down syndrome.  Am J Obstet Gynecol.1991;165:1051-1056.
Shah YG, Eckl CJ, Stinson SK, Woods Jr JR. Biparietal diameter/femur length ratio, cephalic index, and femur length measurements.  Obstet Gynecol.1990;75:186-188.
Verdin SM, Economides DL. The role of ultrasound markers for trisomy 21 in women with positive serum biochemistry.  Br J Obstet Gynaecol.1998;105:63-67.
Vergani P, Locatelli A, Piccoli MG.  et al.  Best second trimester sonographic markers for the detection of trisomy 21.  J Ultrasound Med.1999;18:469-473.
Vibhakar NI, Budorick NE, Scioscia AL.  et al.  Prevalence of aneuploidy with a cardiac intraventricular echogenic focus in an at-risk patient population.  J Ultrasound Med.1999;18:265-268.
Vintzileos AM, Egan JF, Smulian JC.  et al.  Adjusting the risk for trisomy 21 by a simple ultrasound method using fetal long-bone biometry.  Obstet Gynecol.1996;87:953-958.
Watson WJ, Miller RC, Menard MK.  et al.  Ultrasound measurement of fetal nuchal skin to screen for chromosomal abnormalities.  Am J Obstet Gynecol.1994;170:583-586.
Wickstrom E, Maizels M, Sabbagha RE.  et al.  Isolated fetal pyelectasis.  Ultrasound Obstet Gynecol.1996;8:236-240.
Smith-Bindman R, Kerlikowske K, Feldstein VA.  et al.  Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities.  JAMA.1998;280:1510-1517.
Jaeschke R, Guyatt GH, Sackett DL. Users' guides to the medical literature, III: how to use an article about a diagnostic test.  JAMA.1994;271:703-707.
Kuppermann M, Feeny D, Gates E.  et al.  Preferences of women facing a prenatal diagnostic choice.  Prenat Diagn.1999;19:711-716.
Santalahti P, Hemminki E, Latikka AM, Ryynanen M. Women's decision-making in prenatal screening.  Soc Sci Med.1998;46:1067-1076.
Marteau TM. Towards informed decisions about prenatal testing.  Prenat Diagn.1995;15:1215-1226.
Dallaire L, Lortie G, Des Rochers M.  et al.  Parental reaction and adaptability to the prenatal diagnosis of fetal defect or genetic disease leading to pregnancy interruption.  Prenat Diagn.1995;15:249-259.
Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters.  N Engl J Med.1999;341:461-46.
Morris JK, Mutton DE, Ide R.  et al.  Monitoring trends in prenatal diagnosis of Down's syndrome in England and Wales, 1989-92.  J Med Screen.1994;1:233-237.
Lijmer JG, Mol BW, Heisterkamp S.  et al.  Empirical evidence of design-related bias in studies of diagnostic tests.  JAMA.1999;282:1061-1066.

Figures

Figure 1. Fetal Ultrasonographic Markers for Risk of Down Syndrome
Graphic Jump Location
A, Fetal brain with a choroid plexus cyst. B, Fetal neck demonstrating thickening of the nuchal region. C, Bright focus in the fetal heart (echogenic intracardiac focus). D, Dilation of the renal collecting systems (renal pyelectasis). E, Increased brightness in the fetal bowel (echogenic bowel). Humeral and femoral shortening are defined by comparing measurements to a normal distribution and are not illustrated.
Figure 2. Sensitivity and False-Positive Rates (1 − Specificity)
Graphic Jump Location
Data shown for all studies that examined the ultrasonographic markers as screening tests for Down syndrome. One summary estimate is included for each study. The category of "composite findings" was defined differently by each study, but in general included some or all of the markers, in addition to structural abnormalities. Error bars indicate 95% confidence intervals.
Figure 3. Sensitivity for All Studies That Examined Nuchal Fold Thickening
Graphic Jump Location
Data shown for all studies using nuchal fold thickening as a screening test for Down syndrome. Studies are stratified by whether the nuchal fold was evaluated as an isolated abnormality, was seen in conjunction with other abnormalities, or the study did not report whether the nuchal fold was seen as an isolated abnormality (unknown). For studies in which data could be abstracted for both an isolated nuchal fold and for a nuchal fold seen in addition to other abnormalities, 2 data points are included. Size of data markers reflects study sample size; dotted line reflects the point estimates for pooled data.

Tables

Table Graphic Jump LocationTable 1. Description of Included Studies*
Table Graphic Jump LocationTable 2. Investigation of Reasons for Heterogeneity of Studies Examining Nuchal Fold Thickening as a Marker for Down Syndrome (n = 26)
Table Graphic Jump LocationTable 3. Summary Sensitivity and Specificity for Each Ultrasonographic Marker*
Table Graphic Jump LocationTable 4. Summary Accuracy Measures for Each Ultrasonographic Marker When Identified as an Isolated Abnormality*

References

Adams MM, Erickson JD, Layde PM, Oakley GP. Down's syndrome: recent trends in the United States.  JAMA.1981;246:758-760.
Hook EB, Cross PK, Schreinemachers DM. Chromosomal abnormality rates at amniocentesis and in live-born infants.  JAMA.1983;249:2034-2038.
Norton ME. Biochemical and ultrasound screening for chromosomal abnormalities.  Semin Perinatol.1994;18:256-265.
 The California Expanded AFP Screening Program: Prenatal Care Provider Handbook . California Dept of Health Services, Genetic Disease Branch; 1997.
Jones K. Smith's Recognizable Patterns of Human Malformation. 4th ed. Philadelphia, Pa: WB Saunders; 1988.
Waitzman NJ, Romano PS, Scheffler RM. Estimates of the economic costs of birth defects.  Inquiry.1994;31:188-205.
Oberfield RG, Paul H. Prematurity, birth defects, and early death: impact on the family. In: Lewis M, ed. Child and Adolescent Pyschiatry: A Comprehensive Textbook. Baltimore, Md: Williams & Wilkins Co; 1991.
Hook EB, Lindsjö A. Down syndrome in live births by single year maternal age interval in a Swedish study.  Am J Hum Genet.1978;30:19-27.
Canick JA, Knight GJ, Palomaki GE.  et al.  Low second trimester maternal serum unconjugated oestriol in pregnancies with Down's syndrome.  Br J Obstet Gynaecol.1988;95:330-333.
Wald NJ, Cuckle HS, Densem JW.  et al.  Maternal serum screening for Down's syndrome in early pregnancy .  BMJ.1988;297:883-887. [published erratum appears in BMJ. 1988;297:1029].
Wald NJ, Cuckle HS, Densem JW.  et al.  Maternal serum unconjugated oestriol as an antenatal screening test for Down's syndrome.  Br J Obstet Gynaecol.1988;95:334-341.
Palomaki GE, Knight GJ, McCarthy J.  et al.  Maternal serum screening for fetal Down syndrome in the United States: a 1992 survey.  Am J Obstet Gynecol.1993;169:1558-1562.
Haddow JE, Palomaki GE, Knight GJ.  et al.  Prenatal screening for Down's syndrome with use of maternal serum markers.  N Engl J Med.1992;327:588-593.
Haddow JE, Palomaki GE, Knight GJ.  et al.  Second trimester screening for Down's syndrome using maternal serum dimeric inhibin A.  J Med Screen.1998;5:115-119.
The Canadian Early and Mid-trimester Amniocentesis Trial (CEMAT) Group.  Randomised trial to assess safety and fetal outcome of early and midtrimester amniocentesis.  Lancet.1998;351:242-247.
Tabor A, Philip J, Madsen M.  et al.  Randomised controlled trial of genetic amniocentesis in 4606 low-risk women.  Lancet.1986;1:1287-1293.
Greenough A, Yuksel B, Naik S.  et al.  Invasive antenatal procedures and requirement for neonatal intensive care unit admission.  Eur J Pediatr.1997;156:550-552.
Milner AD, Hoskyns EW, Hopkin IE. The effects of mid-trimester amniocentesis on lung function in the neonatal period.  Eur J Pediatr.1992;151:458-460.
 Midtrimester amniocentesis for prenatal diagnosis: safety and accuracy.  JAMA.1976;236:1471-1476.
 An assessment of the hazards of amniocentesis: report to the Medical Research Council by their Working Party on Amniocentesis  Br J Obstet Gynaecol.1978;85 Suppl 2:1-41.
Nicolaides K, Shawwa L, Brizot M, Snijders R. Ultrasoundally detectable markers of fetal chromosomal defects.  Ultrasound Obstet Gynecol.1993;3:56-59.
Nyberg DA, Resta RG, Luthy DA.  et al.  Prenatal sonographic findings of Down syndrome: review of 94 cases.  Obstet Gynecol.1990;76:370-377.
Stoll C, Alembik Y, Dott B.  et al.  Evaluation of prenatal diagnosis of congenital heart disease.  Prenat Diagn.1993;13:453-461.
Davis GK, Farquhar CM, Allan LD.  et al.  Structural cardiac abnormalities in the fetus.  Br J Obstet Gynaecol.1990;97:27-31.
Halliday J, Lumley J, Bankier A. Karyotype abnormalities in fetuses diagnosed as abnormal on ultrasound before 20 weeks' gestational age.  Prenat Diagn.1994;14:689-697.
Hill LM, Guzick D, Belfar HL.  et al.  The current role of sonography in the detection of Down syndrome.  Obstet Gynecol.1989;74:620-623.
Lynch L, Berkowitz GS, Chitkara U.  et al.  Ultrasound detection of Down syndrome.  Obstet Gynecol.1989;73:267-270.
Meagher S, Renshaw R, Smith A, Milligan J. Chromosomal abnormalities detected after an abnormal ultrasound in pregnancy.  Clin Exp Obstet Gynecol.1994;21:215-220.
Chitty LS. Ultrasound screening for fetal abnormalities.  Prenat Diagn.1995;15:1241-1257.
Chew S, Anandakumar C, Jayanthi V.  et al.  Incidence of chromosomal abnormalities in 153 pregnancies with ultrasound detected fetal abnormalities.  Singapore Med J.1996;37:595-597.
Carlson DE, Platt LD. Ultrasound detection of genetic anomalies.  J Reprod Med.1992;37:419-426.
Bernaschek G, Kolankaya A, Stuempflen I, Deutinger J. Chromosomal abnormalities: how much can we predict by ultrasound examination in low-risk pregnancies?  Am J Perinatol.1996;13:259-263.
Chitty LS, Hunt GH, Moore J, Lobb MO. Effectiveness of routine ultrasound in detecting fetal structural abnormalities in a low risk population.  BMJ.1991;303:1165-1169.
Crane JP, LeFevre ML, Winborn RC.  et al.  A randomized trial of prenatal ultrasound screening.  Am J Obstet Gynecol.1994;171:392-399.
Levi S, Schaaps JP, De Havay P.  et al.  End-result of routine ultrasound screening for congenital anomalies.  Ultrasound Obstet Gynecol.1995;5:366-371.
Luck CA. Value of routine ultrasound scanning at 19 weeks.  BMJ.1992;304:1474-1478.
Shirley IM, Bottomley F, Robinson VP. Routine radiographer screening for fetal abnormalities by ultrasound in an unselected low risk population.  Br J Radiol.1992;65:564-569.
Benacerraf BR, Cnann A, Gelman R.  et al.  Can sonographers reliably identify anatomic features associated with Down syndrome in fetuses?  Radiology.1989;173:377-380.
Benacerraf BR. The second-trimester fetus with Down syndrome.  Ultrasound Obstet Gynecol.1996;7:147-155.
Nyberg DA, Luthy DA, Resta RG.  et al.  Age-adjusted ultrasound risk assessment for fetal Down's syndrome during the second trimester.  Ultrasound Obstet Gynecol.1998;12:8-14.
Benacerraf BR, Gelman R, Frigoletto Jr FD. Sonographic identification of second-trimester fetuses with Down's syndrome.  N Engl J Med.1987;317:1371.
Bromley B, Lieberman E, Laboda L, Benacerraf BR. Echogenic intracardiac focus.  Obstet Gynecol.1995;86:998-1001.
Lockwood C, Benacerraf B, Krinsky A.  et al.  A sonographic screening method for Down syndrome.  Am J Obstet Gynecol.1987;157:803-808.
Nyberg DA, Resta RG, Hickok DE.  et al.  Femur length shortening in the detection of Down syndrome.  Am J Obstet Gynecol.1990;162:1247-1252.
Vintzileos AM, Campbell WA, Guzman ER.  et al.  Second-trimester ultrasound markers for detection of trisomy 21.  Obstet Gynecol.1997;89:941-944.
Nadel AS, Bromley B, Frigoletto Jr 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.
Winter TC, Uhrich SB, Souter VL, Nyberg DA. The "genetic sonogram": comparison of the index scoring system with the age-adjusted US risk assessment.  Radiology.2000;215:775-782.
Vintzileos AM, Egan JF. Adjusting the risk for trisomy 21 on the basis of second-trimester ultrasound.  Am J Obstet Gynecol.1995;172:837-844.
Wald NJ, Kennard A, Hackshaw A, McGuire A. Antenatal screening for Down's syndrome.  J Med Screen.1997;4:181-246.
Filly RA. Obstetrical sonography: the best way to terrify a pregnant woman.  J Ultrasound Med.2000;19:1-5.
Irwig L, Macaskill P, Glasziou P, Fahey M. Meta-analytic methods for diagnostic test accuracy.  J Clin Epidemiol.1995;48:119-130.
Deeks JJ. Systematic reviews of evaluations of diagnostic and screening tests. In: Egger M, Smith GD, Altman DG, eds. Systematic Reviews in Health Care: Meta-Analysis in Context. 2nd ed. London, England: BMJ Books; 2001.
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials.1986;7:177-188.
Bahado-Singh RO, Goldstein I, Uerpairojkit B.  et al.  Normal nuchal thickness in the midtrimester indicates reduced risk of Down syndrome in pregnancies with abnormal triple-screen results.  Am J Obstet Gynecol.1995;173:1106-1110.
Bahado-Singh RO, Deren O, Tan A.  et al.  Ultrasoundally adjusted midtrimester risk of trisomy 21 and significant chromosomal defects in advanced maternal age.  Am J Obstet Gynecol.1996;175:1563-1568. [published erratum appears in Am J Obstet Gynecol 1997;176:1400].
Benacerraf BR, Barss VA, Laboda LA. A sonographic sign for the detection in the second trimester of the fetus with Down's syndrome.  Am J Obstet Gynecol.1985;151:1078-1079.
Benacerraf BR, Frigoletto Jr FD, Cramer DW. Down syndrome: sonographic sign for diagnosis in the second-trimester fetus.  Radiology.1987;163:811-813.
Benacerraf BR, Neuberg D, Frigoletto Jr FD. Humeral shortening in second-trimester fetuses with Down syndrome.  Obstet Gynecol.1991;77:223-227.
Benacerraf BR, Neuberg D, Bromley B, Frigoletto Jr FD. Sonographic scoring index for prenatal detection of chromosomal abnormalities.  J Ultrasound Med.1992;11:449-458.
Benacerraf BR, Nadel A, Bromley B. Identification of second-trimester fetuses with autosomal trisomy by use of a sonographic scoring index.  Radiology.1994;193:135-140.
Biagiotti R, Periti E, Cariati E. Humerus and femur length in fetuses with Down syndrome.  Prenat Diagn.1994;14:429-434.
Borrell A, Costa D, Martinez JM.  et al.  Criteria for fetal nuchal thickness cut-off.  Prenat Diagn.1997;17:23-29.
Boyd PA, Chamberlain P, Hicks NR. 6-Year experience of prenatal diagnosis in an unselected population in Oxford, UK.  Lancet.1998;352:1577-1581.
Bromley B, Lieberman E, Benacerraf BR. The incorporation of maternal age into the sonographic scoring index for the detection at 14-20 weeks of fetuses with Down's syndrome.  Ultrasound Obstet Gynecol.1997;10:321-324.
Brumfield CG, Hauth JC, Cloud GA.  et al.  Sonographic measurements and ratios in fetuses with Down syndrome.  Obstet Gynecol.1989;73:644-646.
Campbell WA, Vintzileos AM, Rodis JF.  et al.  Efficacy of the biparietal diameter/femur length ratio to detect Down syndrome in patients with an abnormal biochemical screen.  Fetal Diagn Ther.1994;9:175-182.
Chan L, Hixson JL, Laifer SA.  et al.  A sonographic and karyotypic study of second-trimester fetal choroid plexus cysts.  Obstet Gynecol.1989;73:703-706.
Crane JP, Gray DL. Sonographically measured nuchal skinfold thickness as a screening tool for Down syndrome.  Obstet Gynecol.1991;77:533-536.
Cuckle H, Wald N, Quinn J.  et al.  Ultrasound fetal femur length measurement in the screening for Down's syndrome.  Br J Obstet Gynaecol.1989;96:1373-1378.
Deren O, Mahoney MJ, Copel JA, Bahado-Singh RO. Subtle ultrasound anomalies.  Am J Obstet Gynecol.1998;178:441-445.
DeVore GR, Alfi O. The use of color Doppler ultrasound to identify fetuses at increased risk for trisomy 21.  Obstet Gynecol.1995;85:378-386.
Dicke JM, Gray DL, Songster GS, Crane JP. Fetal biometry as a screening tool for the detection of chromosomally abnormal pregnancies.  Obstet Gynecol.1989;74:726-729.
Donnenfeld AE, Carlson DE, Palomaki GE.  et al.  Prospective multicenter study of second-trimester nuchal skinfold thickness in unaffected and Down syndrome pregnancies.  Obstet Gynecol.1994;84:844-847.
D'Ottavio G, Meir YJ, Rustico MA.  et al.  Screening for fetal anomalies by ultrasound at 14 and 21 weeks.  Ultrasound Obstet Gynecol.1997;10:375-380.
Drugan A, Johnson MP, Reichler A.  et al.  Second-trimester minor ultrasound anomalies.  Obstet Gynecol.1996;88:203-206.
Ginsberg N, Cadkin A, Pergament E, Verlinsky Y. Ultrasound detection of the second-trimester fetus with trisomy 18 and trisomy 21.  Am J Obstet Gynecol.1990;163:1186-1190.
Grandjean H, Sarramon MF. Femur/foot length ratio for detection of Down syndrome.  Am J Obstet Gynecol.1995;173:16-19.
Grandjean H, Sarramon MF. Sonographic measurement of nuchal skinfold thickness for detection of Down syndrome in the second-trimester fetus.  Obstet Gynecol.1995;85:103-106.
Gray DL, Winborn RC, Suessen TL, Crane JP. Is genetic amniocentesis warranted when isolated choroid plexus cysts are found?  Prenat Diagn.1996;16:983-990.
Gray DL, Crane JP. Optimal nuchal skin-fold thresholds based on gestational age for prenatal detection of Down syndrome.  Am J Obstet Gynecol.1994;171:1282-1286.
Grist TM, Fuller RW, Albiez KL, Bowie JD. Femur length in the US prediction of trisomy 21 and other chromosomal abnormalities.  Radiology.1990;174:837-839.
Johnson MP, Barr Jr M, Treadwell MC.  et al.  Fetal leg and femur/foot length ratio: a marker for trisomy 21.  Am J Obstet Gynecol.1993;169:557-563.
Johnson MP, Michaelson JE, Barr Jr M.  et al.  Combining humerus and femur length for improved ultrasound identification of pregnancies at increased risk for trisomy 21.  Am J Obstet Gynecol.1995;172:1229-1235.
LaFollette L, Filly RA, Anderson R, Golbus MS. Fetal femur length to detect trisomy 21.  J Ultrasound Med.1989;8:657-660.
Lockwood CJ, Lynch L, Ghidini A.  et al.  The effect of fetal gender on the prediction of Down syndrome by means of maternal serum alpha-fetoprotein and ultrasound parameters.  Am J Obstet Gynecol.1993;169:1190-1197.
Manning JE, Ragavendra N, Sayre J.  et al.  Significance of fetal intracardiac echogenic foci in relation to trisomy 21.  AJR Am J Roentgenol.1998;170:1083-1084.
Marquette GP, Boucher M, Desrochers M, Dallaire L. Screening for trisomy 21 with ultrasound determination of biparietal diameter/femur length ratio.  Am J Obstet Gynecol.1990;163:1604-1605.
Nicolaides KH, Snijders RJ, Gosden CM.  et al.  Ultrasoundally detectable markers of fetal chromosomal abnormalities.  Lancet.1992;340:704-707.
Nyberg DA, Resta RG, Luthy DA.  et al.  Humerus and femur length shortening in the detection of Down's syndrome.  Am J Obstet Gynecol.1993;168:534-538.
Nyberg DA, Luthy DA, Cheng EY.  et al.  Role of prenatal ultrasound in women with positive screen for Down syndrome on the basis of maternal serum markers.  Am J Obstet Gynecol.1995;173:1030-1035.
Rodis JF, Vintzileos AM, Fleming AD.  et al.  Comparison of humerus length with femur length in fetuses with Down syndrome.  Am J Obstet Gynecol.1991;165:1051-1056.
Shah YG, Eckl CJ, Stinson SK, Woods Jr JR. Biparietal diameter/femur length ratio, cephalic index, and femur length measurements.  Obstet Gynecol.1990;75:186-188.
Verdin SM, Economides DL. The role of ultrasound markers for trisomy 21 in women with positive serum biochemistry.  Br J Obstet Gynaecol.1998;105:63-67.
Vergani P, Locatelli A, Piccoli MG.  et al.  Best second trimester sonographic markers for the detection of trisomy 21.  J Ultrasound Med.1999;18:469-473.
Vibhakar NI, Budorick NE, Scioscia AL.  et al.  Prevalence of aneuploidy with a cardiac intraventricular echogenic focus in an at-risk patient population.  J Ultrasound Med.1999;18:265-268.
Vintzileos AM, Egan JF, Smulian JC.  et al.  Adjusting the risk for trisomy 21 by a simple ultrasound method using fetal long-bone biometry.  Obstet Gynecol.1996;87:953-958.
Watson WJ, Miller RC, Menard MK.  et al.  Ultrasound measurement of fetal nuchal skin to screen for chromosomal abnormalities.  Am J Obstet Gynecol.1994;170:583-586.
Wickstrom E, Maizels M, Sabbagha RE.  et al.  Isolated fetal pyelectasis.  Ultrasound Obstet Gynecol.1996;8:236-240.
Smith-Bindman R, Kerlikowske K, Feldstein VA.  et al.  Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities.  JAMA.1998;280:1510-1517.
Jaeschke R, Guyatt GH, Sackett DL. Users' guides to the medical literature, III: how to use an article about a diagnostic test.  JAMA.1994;271:703-707.
Kuppermann M, Feeny D, Gates E.  et al.  Preferences of women facing a prenatal diagnostic choice.  Prenat Diagn.1999;19:711-716.
Santalahti P, Hemminki E, Latikka AM, Ryynanen M. Women's decision-making in prenatal screening.  Soc Sci Med.1998;46:1067-1076.
Marteau TM. Towards informed decisions about prenatal testing.  Prenat Diagn.1995;15:1215-1226.
Dallaire L, Lortie G, Des Rochers M.  et al.  Parental reaction and adaptability to the prenatal diagnosis of fetal defect or genetic disease leading to pregnancy interruption.  Prenat Diagn.1995;15:249-259.
Wald NJ, Watt HC, Hackshaw AK. Integrated screening for Down's syndrome on the basis of tests performed during the first and second trimesters.  N Engl J Med.1999;341:461-46.
Morris JK, Mutton DE, Ide R.  et al.  Monitoring trends in prenatal diagnosis of Down's syndrome in England and Wales, 1989-92.  J Med Screen.1994;1:233-237.
Lijmer JG, Mol BW, Heisterkamp S.  et al.  Empirical evidence of design-related bias in studies of diagnostic tests.  JAMA.1999;282:1061-1066.

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 150

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles