A model for second-trimester Down syndrome sonographic screening based on facial landmarks and digit length measurement.

OBJECTIVE: To determine whether Down syndrome can be detected by combining measurements of fetal nasal bone (NB) length, prenasal thickness (PT) and digits 2 and 3 of the hand. METHODS: Two hundred and fifty-four normal and 25 Down-syndrome fetuses were scanned between 15 and 33 weeks' gestation. Physicians performing the scans were not blinded to the fetal karyotype. Both PT and NB were measured in a mid-sagittal plane. For PT measurement calipers were placed between the frontonasal angle and the outer skin edge. Digits 2 and 3 of one hand were also measured. The results (except for PT/NB ratio) were expressed in multiples of the normal gestation-specific median (MoM). A logistic regression model was used to estimate the odds of the fetus having Down syndrome given different combinations of NB, PT, PT/NB ratio, and digits 2 and 3 measurements. The odds were used to calculate the risk of Down syndrome for each pregnant woman from her age and measurements. RESULTS: The median PT MoM for unaffected fetuses and Down-syndrome fetuses was 1.12 vs. 1.35 (P < 0.0001). The median NB MoM for unaffected and Down-syndrome fetuses was 1.03 vs. 0.81 (P < 0.001) and the PT/NB ratio MoM for unaffected and Down-syndrome fetuses was 0.63 vs. 0.96 (P < 0.001). The respective median MoM values for digits 2 and 3 of the Down-syndrome fetuses were significantly smaller (0.81 vs. 0.93 and 0.89 vs. 0.95, respectively, P = 0.003). Only the PT/NB ratio and digit 2 were finally included in the logistic regression equation. Using a 1 in 200 risk cut-off, the observed sensitivity and false-positive rate were 76% and 6.7%, respectively. CONCLUSION: Combining the PT/NB ratio and digit 2 measurements yielded a promising screening detection rate. Confirmation of our findings in a prospective study is needed before the method can be used clinically.     

Hypoplasia of the middle phalanx of the fifth digit. A feature of the second trimester fetus with Down's syndrome

It has been established that 60% of infants with Down's syndrome have hypoplasia of the middle phalanx of the fifth digit. To determine whether this would be a useful prenatal sonographic sign for Down's syndrome, we measured the middle phalanx of the fifth and fourth digits in 1,032 fetuses between 15 and 20 weeks gestational age at the time of amniocentesis, prior to any knowledge of the karyotypes. A ratio of the middle phalanx of the fifth digit over the middle phalanx of the fourth digit was calculated, and the median ratio for the 1,024 normal fetuses was 0.85. There were eight fetuses who had trisomy 21 by karyotype and their median ratio was 0.59 (P = .04). Of the eight fetuses with Down's syndrome, seven had ratios below the normal population median. If an arbitrary cut-off point is used at a ratio of 0.70, 6/8 (75%) of those with Down's syndrome would be identified, as well as 18% of normal fetuses (positive predictive value = 3.2% in this group). Although we do not suggest that this ratio be used alone as a screening test for Down's syndrome, these findings confirm the presence of a small middle phalanx in fetuses with trisomy 21 as early as 15 to 16 weeks and may be a useful adjunct to the several already reported sonographic signs in the fetus at risk for Down's syndrome.     

Nuchal translucence incorporated into a one-stage multifactorial screening model for Down syndrome prediction at second-trimester pregnancy

The aim of this study was to achieve one-stage screening for trisomy 21 using a combination of nuchal translucency (NuT) measurement and maternal serum alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (hCG) biochemistry levels in the second trimester among a high-risk study population. From January 1998 to June 2001, 45 cases of trisomy 21 were prenatally found and confirmed in the hospital-based cytogenetic diagnosis laboratory. A total of 867 normal singleton pregnancies were enrolled as controls from the antenatal care clinics in the hospital. All study and control subjects between 13 weeks and 18 weeks of gestation with a mean age of 15.2 +/- 1.3 weeks underwent one-stage nuchal translucence measurements and maternal serum biochemical screening for Down syndrome. The final logistic model contained beta-hCG (multiples of the gestational median or MoM), maternal age (matA), nuchal translucence (NuT MoM) and AFP (MoM) as covariates. Also, the estimated coefficients of the regression were highly significant. This model provided the estimated probability of Down syndrome as follows: Pr (Down syndrome) = exp (Z)/ [1 + exp (Z)], where Z = -11.18 + 0.64 x (beta-hCG MoM) + 0.25 x matA + 1.32 x NuT MoM -2.23 x AFP MoM. The logistic regression with estimated coefficients was installed in a Palm digital assistant (PDA) equipped with Excel (Microsoft). The risk probability of Down syndrome could be readily calculated after inputting data for all four predictor variables.     

Fetuses with Down syndrome have an enlarged anterior fontanelle in the second trimester of pregnancy.

OBJECTIVE: Neonates with Down syndrome are known to have an enlarged anterior fontanelle. The aim of this study was to assess whether fetuses diagnosed with Down syndrome in the second trimester have larger anterior fontanelles in comparison with normal euploid fetuses. METHODS: The study population included 13 fetuses with trisomy 21 and 26 normal euploid fetuses analyzed between the 19(th) and the 23(rd) weeks of gestation. The anterior fontanelle was assessed by three-dimensional ultrasound, with the midsagittal plane of the fetal head being the reference view for acquisition of the volume. Anteroposterior and laterolateral diameters, perimeter and area of the fontanelle were then measured offline; the diameters were normalized for biparietal diameter and the perimeter and area were normalized for head circumference. Non-parametric statistical analysis was used to compare the mean values of all variables in the two groups of fetuses. Intra- and interobserver variability were also assessed. RESULTS: All variables except the fontanelle laterolateral diameter were significantly greater in Down syndrome fetuses than in controls, with anterior fontanelle perimeter/head circumference and fontanelle area/head circumference ratios showing the highest sensitivity for the detection of Down syndrome. Using a cut-off of 2.1 for the fontanelle area/head circumference ratio, the sensitivity and specificity for the detection of Down syndrome were 77% and 96%, respectively. CONCLUSION: During the mid-trimester the dimensions of the anterior fontanelle are significantly increased in fetuses with Down syndrome in comparison with normal euploid fetuses. This finding may be of help in the detection of trisomy 21 at the time of the anomaly scan.     

Fetal nose bone length: a marker for Down syndrome in the second trimester.

OBJECTIVE: To evaluate the significance of nasal bone length in relation to the detection of Down syndrome in the second trimester. METHODS: We evaluated consecutive fetuses referred to our facility between 15 and 20 weeks' gestation for sonography and amniocentesis because of an increased risk of aneuploidy. A detailed structural survey, biometric measurements, and measurement of the nasal bone were obtained at the time of amniocentesis and subsequently compared with karyotype. The characteristics of the fetuses with Down syndrome were compared with those of the euploid fetuses. RESULTS: A total of 239 fetuses were evaluated. Sixteen fetuses (7%) had Down syndrome, and 223 were euploid. In fetuses with Down syndrome, 6 (37%) of 16 did not have detectable nose bones, compared with 1 (0.5%) of 223 control fetuses, yielding a likelihood ratio of 83. Detectable nasal bones were seen in 10 fetuses with Down syndrome and 222 euploid fetuses. A receiver operating characteristic curve for the biparietal diameter-nasal bone length ratio showed that a value of 9 or greater detected 100% of fetuses with Down syndrome and 22% of euploid fetuses. If the ratio were 10 or greater, then 81 % fetuses with Down syndrome and 11 % of euploid fetuses would have been identified. If the ratio were 11 or greater, 69% of fetuses with Down syndrome would be identified, compared with 5% of euploid fetuses. CONCLUSIONS: The absence of a nasal bone is a powerful marker for Down syndrome. A short nasal bone is associated with an increased likelihood for fetal Down syndrome in a high-risk population.     

Fetal aberrant right subclavian artery in normal and Down syndrome fetuses.

OBJECTIVES: To evaluate the prevalence of fetal aberrant right subclavian artery (ARSA) in a low-risk population and compare it with that among Down syndrome fetuses, in order to estimate its potential as a marker in Down syndrome screening. METHODS: Women undergoing routine fetal sonographic examination between 13 and 26 weeks of gestation were evaluated once for the presence of ARSA using either a transvaginal multifrequency 5-9-MHz probe or a transabdominal 4-8-MHz probe as appropriate. Early pregnancy outcome was obtained in all cases. RESULTS: Nine hundred and twenty-four fetuses were recruited. An ARSA was detected in 13 fetuses (1.4%) with normal karyotype. During the study period, eight fetuses with Down syndrome referred either with known karyotype or with signs suspicious for Down syndrome were evaluated by the same protocol. Three of eight fetuses (37.5%) were found to have an ARSA. In none of these cases was ARSA an isolated finding. The odds ratio for ARSA in Down syndrome compared with normal fetuses was 42.04 (95% CI, 9.08-194.6). CONCLUSIONS: An ARSA was found in 1.4% of the normal population. In the small group of Down syndrome fetuses we observed a trend towards a higher rate of ARSA than in normal fetuses. In none of the Down syndrome fetuses was ARSA an isolated finding. Larger prospective studies are needed to examine the significance of ARSA as an isolated finding and the potential of ARSA as a marker in Down syndrome screening.     

Electrodiagnosis of mild carpal tunnel syndrome

Electrophysiologic tests have been reported to detect mild carpal tunnel syndrome (CTS). Such tests include (i) absolute palmar latency of median wrist segment; (ii) comparison of median and radial distal sensory latencies in digit I; (iii) comparison of median and ulnar distal sensory latencies in digit IV; (iv) comparison of median and ulnar palmar latencies; (v) comparison of median and ulnar sensory potential amplitudes in digits II and V. To clarify the clinical utility of these tests, the parameters of all five tests were determined across four carefully established patient subgroups: group A, controls; group B, CTS referrals with normal nerve conduction studies (NCS) and normal needle electromyography (EMG); group C, CTS referrals with abnormal NCS and normal EMG; group D, CTS referrals with abnormal NCS and abnormal EMG. Special attention was focused on patients in group B who represent the diagnostic dilemma. In group B, tests ii and iii each yielded abnormal results in 44% of hands, while the combination of tests ii and iii yielded abnormal results in 51% of hands.     

A histological and radiological investigation of the nasal bone in fetuses with Down syndrome.

OBJECTIVES: Previous studies of nasal bone development in Down syndrome have used radiographs or ultrasound for the detection of nasal bone length or nasal bone absence. The aim of this study was to investigate the presence and size of the nasal bones in postmortem Down syndrome fetuses by means of radiographs and histological examination. METHODS: Thirty-three aborted human fetuses (gestational age 14-25 weeks) with Down syndrome were included. A mid-sagittal tissue block was excised from the skull base to the foramen magnum and along the lateral aspect of the spine. Radiographs of the tissue block were taken in lateral, frontal and axial projections. The length of the nasal bone was measured. The tissue blocks were cut in serial sections and stained. The crown-rump length (CRL), foot length (FL) and number of ossified bones in the hand and foot (CNO) were recorded. RESULTS: A total of 8/33 fetuses had bilateral nasal bone absence and two had unilateral absence. In fetuses with radiographically diagnosed nasal bone absence, no nasal bone could be found histologically. The majority of the Down syndrome fetuses had CRL, FL and CNO values within the range of those for normal age-matched fetuses. Nasal bone length was normal or reduced. CONCLUSIONS: Absence of the nasal bone was registered by postmortem examination in one-third of fetuses with Down syndrome. In some fetuses this could be a result of delayed maturation associated with Down syndrome. The phenotypic differences in nasal bone appearance may reflect genotypic differences in the Down syndrome group.     

Management of Kell isoimmunization--evaluation of a Doppler-guided approach.

OBJECTIVE: To assess the role of peak systolic velocity in the middle cerebral artery (MCA-PSV) in the management of pregnancies complicated by Kell isoimmunization. METHODS: Sixteen fetuses were monitored by conventional protocol (Group 1) and eight fetuses by an MCA-PSV-guided protocol (Group 2). The conventional protocol included a weekly ultrasound evaluation and measurement of maternal anti-Kell titers every 4-6 weeks. In Group 2 Doppler assessment of the MCA-PSV was performed at intervals of 4 to 7 days and MCA-PSV>1.5 multiples of the median (MoM) was considered as an indication for fetal blood sampling (FBS). RESULTS: No parameter emerged as a reliable predictor of isoimmunization severity in Group 1. In Group 2, no FBS was necessary in one case since the MCA-PSV values obtained during the follow-up were <1.29 MoM. In two cases the first FBS was already indicated after 1 week of follow-up, but five other fetuses were followed for 3-9 weeks before FBS was indicated. All fetuses with MCA-PSV>1.5 MoM prior to intrauterine transfusion (IUT) had severe fetal anemia on FBS. In fetuses with severe anemia on the first FBS, the MCA-PSV values 7 days before the first FBS were <1.29 MoM (four cases), between 1.29 and 1.5 MoM (two cases) and >1.55 MoM (one case). CONCLUSIONS: In the management of Kell isoimmunization invasive procedures may be avoided by implementing MCA-PSV measurements. Delineation of appropriate intervals between reassessments, the reliability of MCA-PSV following repeated IUTs, and cut-off values for FBS await further study.     

Prenatal age-specific reference intervals for measuring all five digits of the fetal hand.

OBJECTIVE: To construct prenatal age-specific reference intervals for measurement of five digits in normal fetuses. PATIENTS AND METHODS: Prospective cross-sectional study of fetuses assessed at an antenatal ultrasound unit in a university-affiliated general hospital. The study cohort comprised 302 pregnant women attending our clinic for routine fetal biometry or anomaly scan between December 1997 and June 2000. They all fulfilled the study inclusion criteria: singleton fetuses with normal anatomy, accurate gestational age and no medical complications of pregnancy. Each fetus was scanned once only and the finger measurements of one hand were obtained. Electronic calipers were placed on the outer margin of the proximal phalanx to the outer margin of the distal phalanx level. Those measurements and the relevant gestational age were registered in a computerized database. RESULTS: The linear increase of size of each of the five fingers was plotted across the evaluated range of gestation (P < 0.001; r2 between 0.85 and 0.86 for fingers I to V). Tables showing the 5th, 50th and 95th centiles of finger lengths between 14 and 27 weeks' gestation were created based on the reference interval charts. CONCLUSIONS: Second-trimester measurement of all five digits of the fetal hand is feasible. This may assist in the evaluation of fetuses that are primarily suspected of having genetic abnormalities that might be expressed by deviation in finger length.     

Nuchal translucency in fetuses affected by homozygous alpha-thalassemia-1 at 12-13 weeks of gestation.

OBJECTIVE: Fetuses affected by homozygous alpha-thalassemia-1 are anemic in the first trimester. We studied their nuchal translucency (NT) measurements at 12-13 weeks of gestation. METHODS: Nuchal translucency was measured prospectively in fetuses at risk of homozygous alpha-thalassemia-1. Measurements of those fetuses subsequently confirmed to be affected by homozygous alpha-thalassemia-1 but with a normal karyotype were compared to those of 440 controls. The controls were from the general obstetric population who had NT measurements at 12 or 13 weeks with known normal outcome. All the NT measurements were expressed as multiples of the median (MoM) for the gestational day. RESULTS: Between 1996 and 1998, 94 at-risk pregnancies were studied. Of these, 32 were subsequently confirmed to be affected by homozygous alpha-thalassemia-1. Chromosome study was not carried out in three cases and these were excluded from the analysis. Nuchal translucency MoMs for cases and controls were found to fit a log Gaussian distribution. The log means (standard deviation) for case and control NT MoM were 0.075 (0.156) and -0.0019 (0.091), respectively. The median NT MoM (95% CI) for cases was 1.19 (1.08-1.62) and was significantly higher than that of the controls (p < 0.001). However, there was extensive overlap of NT between cases and controls. CONCLUSION: Overall, there was a 19% increase in NT MoM in fetuses affected by homozygous alpha-thalassemia-1. This represents a difference of only 0.3-0.4 mm, which is clinically insignificant. This finding indirectly suggests that the increased NT in trisomic fetuses cannot be explained by fetal anemia. Conversely, the presence of increased NT in a fetus at risk of homozygous alpha-thalassemia-1 should alert one to the possibility of chromosomal abnormality rather than being attributed to fetal anemia.     

Model‐Predicted Performance of Second‐Trimester Down Syndrome Screening With Sonographic Prenasal Thickness

Objective. The purpose of this study was to estimate the Down syndrome detection and false‐positive rates for second‐trimester sonographic prenasal thickness (PT) measurement alone and in combination with other markers. Methods. Multivariate log Gaussian modeling was performed using numerical integration. Parameters for the PT distribution, in multiples of the normal gestation‐specific median (MoM), were derived from 105 Down syndrome and 1385 unaffected pregnancies scanned at 14 to 27 weeks. The data included a new series of 25 cases and 535 controls combined with 4 previously published series. The means were estimated by the median and the SDs by the 10th to 90th range divided by 2.563. Parameters for other markers were obtained from the literature. Results. A log Gaussian model fitted the distribution of PT values well in Down syndrome and unaffected pregnancies. The distribution parameters were as follows: Down syndrome, mean, 1.334 MoM; log₁₀ SD, 0.0772; unaffected pregnancies, 0.995 and 0.0752, respectively. The model‐predicted detection rates for 1%, 3%, and 5% false‐positive rates for PT alone were 35%, 51%, and 60%, respectively. The addition of PT to a 4–serum marker protocol increased detection by 14% to 18% compared with serum alone. The simultaneous sonographic measurement of PT and nasal bone length increased detection by 19% to 26%, and with a third sonographic marker, nuchal skin fold, performance was comparable with first‐trimester protocols. Conclusions. Second‐trimester screening with sonographic PT and serum markers is predicted to have a high detection rate, and further sonographic markers could perform comparably with first‐trimester screening protocols.     

Relationship between fetal nuchal translucency and crown-rump length in an Asian population.

OBJECTIVES: To investigate the relationship between the nuchal translucency (NT) thickness and crown-rump length (CRL) in normal Asian fetuses during the first trimester. DESIGN: A prospective observational study was conducted. Ultrasound measurement of NT and CRL was offered in 879 consecutive Taiwanese fetuses between 9 weeks and 14 weeks of gestation. Regression analysis was used to analyze the relationship between the NT thickness and CRL. Fetal sex was also considered in the analysis. The distribution of multiple of median (MoM) values of the NT measurements with CRL in 10-mm intervals and the 95th centile of MoM were also calculated. RESULTS: The present study shows that NT measurements increase with increasing CRL. A fixed cut-off point through the first trimester is not appropriate. The NT thickness has no relationship with fetal sex. Expressing the NT thickness by MoM values provides a simple method for clinical practice. CONCLUSIONS: The present study offers normative data of the fetal NT thickness in an Asian population, which may improve the performance of NT measurement during the first-trimester as a screening tool for chromosomal aberrations or other congenital abnormalities in the first trimester.     

Maternal serum invasive trophoblast antigen and first-trimester Down syndrome screening

BACKGROUND: In the United States, Down syndrome screening is still performed mainly in the second trimester, using 3 or 4 markers. Moving screening into the first trimester has the advantage of earlier diagnosis. Currently, first-trimester screening typically includes maternal serum pregnancy-associated plasma protein-A (PAPP-A), the free beta-subunit of human chorionic gonadotropin (free beta), and ultrasound measurement of nuchal translucency thickness (NT). The current report describes a case-control study of serum invasive trophoblast antigen (ITA) and its possible inclusion in first-trimester screening for Down syndrome. METHODS: As part of an earlier observational study, serum samples from 54 Down syndrome and 276 matched unaffected pregnancies were collected between 9 and 15 weeks of gestation. Samples had been aliquoted and stored at -20 degrees C for 8 years. ITA was measured and converted to weight-adjusted multiples of the median (MoM). The distributions of other first-trimester markers are from a single published study. RESULTS: Median ITA MoM in Down syndrome pregnancies increase as gestational age increases (2.02 MoM at 11 and 2.44 MoM at 13 completed weeks). At 75% detection, maternal age in combination with ITA and PAPP-A measurements have an 8.0% false-positive rate, slightly lower than the 8.8% found for the free beta and PAPP-A combination; adding NT measurements reduces false positives for the 2 combinations to 2.0% and 1.8%, respectively. CONCLUSION: Serum ITA appears to be a useful first-trimester Down syndrome marker that could replace free beta measurements while maintaining performance.     

Evaluation of cell-free fetal DNA as a second-trimester maternal serum marker of Down syndrome pregnancy

BACKGROUND: Second-trimester cell-free fetal DNA (studied only in pregnancies with male fetuses) is higher in maternal serum samples from women carrying Down syndrome fetuses than in unaffected pregnancies. In this study we evaluated the potential performance of fetal DNA as a screening marker for Down syndrome. METHODS: Data on maternal serum fetal DNA concentrations and the corresponding concentrations of the quadruple serum markers were available from 15 Down syndrome cases, each matched for gestational age and length of freezer storage, with 5 control samples. Analyte values were expressed as multiple(s) of the control or population median. Screening performance of fetal DNA, both alone and when added to estimates of quadruple marker performance, was determined after modeling using univariate and multivariate gaussian distribution analysis. RESULTS: The median fetal DNA concentration in Down syndrome cases was 1.7 times higher than in controls. In univariate analysis, fetal DNA gave a 21% detection rate at a 5% false-positive rate. When added to quadruple marker screening, fetal DNA increased the estimated detection rate from 81% to 86% at a 5% false-positive rate. CONCLUSIONS: Cell-free fetal DNA, measured in maternal serum, can modestly increase screening performance above what is currently available in the second trimester. If and when maternal serum fetal DNA can be measured in pregnancies with both male and female fetuses, the utility and cost-effectiveness of adding it as a Down syndrome screening marker should be assessed.     

The genetic sonogram: a method of risk assessment for Down syndrome in the second trimester.

OBJECTIVE: To determine the risk of Down syndrome in fetuses with sonographic markers using the Bayes theorem and likelihood ratios. METHODS: We prospectively evaluated the midtrimester sonographic features of fetuses with Down syndrome and compared them with euploid fetuses. Patients were referred for an increased risk of aneuploidy and evaluated for the presence of structural defects, a nuchal fold, short long bones, pyelectasis, an echogenic intracardiac focus, and hyperechoic bowel. All fetuses underwent amniocentesis at the time of sonographic assessment. The sensitivity, specificity, and likelihood ratios for markers were calculated both as nonisolated and isolated findings. RESULT: There were 164 fetuses with Down syndrome and 656 euploid fetuses. The presence of any marker resulted in sensitivity for the detection of Down syndrome of 80.5% with a false-positive rate of 12.4%. The absence of any markers conferred a likelihood ratio of 0.2, decreasing the risk of Down syndrome by 80%. As an isolated marker, the nuchal fold had an "infinite" likelihood ratio for Down syndrome; a short humerus had a likelihood ratio of 5.8, whereas structural anomalies had a likelihood ratio of 3.3. Other isolated markers had low likelihood ratios because of the higher prevalence in the unaffected population. The likelihood ratios for the presence of 1, 2, and 3 of any of the markers were 1.9, 6.2, and 80, respectively. CONCLUSIONS: Although an isolated marker with a low likelihood ratio may not increase a patient's risk of Down syndrome, the presence of such a marker precludes reducing the risk of aneuploidy. Clusters of markers appear to confer a higher risk.     

Fetal breasts in normal and down syndrome fetuses

To assess the validity of fetal breast size measurement as a sonographic marker in fetuses with Down syndrome. Methods: Fetal breasts were studied in 26 fetuses with trisomy 21 and 78 fetuses with normal chromosomes. Breasts were identified and measured in a cross-sectional plane of the fetal chest at the level of the four-chamber view of the heart. Normal fetuses had a mean breast size of 3.8 mm ± 1.1 mm. Fetuses with Down syndrome had a mean breast size of 1.9 mm ± 0.7 mm (p ⩽ 0.0001). Diminished breast size measured by ultrasound in the second trimester may be helpful in identifying fetuses with Down syndrome. © 1996 John Wiley & Sons, Inc.     

Outcome validation of the Beckman Coulter access analyzer in a second-trimester Down syndrome serum screening application

BACKGROUND: Mid-trimester maternal serum alpha-fetoprotein (AFP) and unconjugated estriol (uE3) are 30% lower and human chorionic gonadotropin (hCG) is twofold higher in Down syndrome pregnancies compared with unaffected pregnancies. In maternal serum screening, patient-specific risks are calculated using published gaussian frequency distribution parameters for these three markers obtained with previously available immunoassays. New immunoassays must generate similar distribution parameters if the accuracy of assigned risks and overall performance of prenatal screening are to be maintained. METHODS: Agreement between the Beckman Coulter Access and the Bayer Immuno 1 assays for AFP and hCG and the Amersham Amerlex-M RIA for uE3 was assessed in 558 fresh sera. Precision was measured over 6 weeks. Median concentrations were calculated by regression of 568 Caucasian singleton pregnancy samples against gestational age in days. Frozen mid-trimester sera from 44 confirmed Down syndrome singleton pregnancies (cases) were selected without conscious bias for reanalysis, and each case was matched with five control specimens from unaffected pregnancies. Serum markers were expressed as the multiple of the median (MoM) concentration derived from the control samples, corrected for maternal weight and converted to their log-equivalent values. Normality was assessed using probability plots and the Shapiro-Wilk W-test. Gaussian distribution parameters were compared with established values, and Down syndrome risk calculations were assessed with a commonly used risk algorithm. RESULTS: The Access AFP and hCG assays had consistent proportional agreement with the established assays, whereas agreement between the uE3 methods was less consistent. Analytical imprecision was 3-6% at mid-trimester concentrations. Normal distributions were obtained for the log MoM values of all three markers in both the Down syndrome and unaffected populations, and their gaussian distribution parameters compared well with established values. The performance of the Access assays in an established trivariate risk algorithm for Down syndrome was equal to the performance exhibited by traditional methods. CONCLUSION: The Beckman Coulter Access analyzer provides valid mid-trimester serum AFP, uE3, and hCG results and risk assessments when applied in a prenatal Down syndrome screening service.     

Screening for trisomy 21 during the routine second-trimester ultrasound examination in an unselected Chilean population.

OBJECTIVE: To evaluate the performance of a detailed ultrasound examination during the second trimester as a screening test for Down syndrome in an unselected Chilean population. METHODS: This was part of an ongoing longitudinal study. Included were 3071 women with singleton pregnancies who underwent routine ultrasound examination between 21 + 0 and 25 + 6 gestational weeks as a screening test for chromosomal abnormalities and major congenital structural defects, and who were diagnosed as having trisomy 21 or being chromosomally normal. Maternal age, and eight soft markers and cardiac defects associated with Down syndrome were evaluated as a screening test using logistic regression analysis. RESULTS: The incidence of Down syndrome was 0.6%, and the mean maternal age was 29.4 +/- 6.2 years. At least one of four soft markers (absent nasal bone, nuchal edema, short femur, echogenic foci) and/or cardiac defects was present in 77.8% of Down syndrome fetuses and in 3.1% of normal fetuses. Furthermore, with a false-positive rate of 1%, the detection rate using the combined model of ultrasound markers and maternal age was 72.2%. CONCLUSIONS: Second-trimester ultrasound markers are able to detect over 70% of Down syndrome fetuses with only a 1% false-positive rate.     

Genetic sonogram scoring index: accuracy and clinical utility.

We sought to evaluate the accuracy of the genetic sonogram scoring index in detecting Down syndrome fetuses in a high-risk population. Women referred for genetic sonogram scoring index based on increased risk for aneuploidy were prospectively evaluated. Each fetus was assigned a score based on our previously published genetic sonogram scoring index. A score of 1 or greater was an indication for karyotype determination. Of 1076 patients (1118 fetuses) in the study group, follow-up data were available for 1030 (92%), eight of whom had Down syndrome (prevalence 0.8%). Three fetuses with Down syndrome had a genetic sonogram scoring index of 0, and for one of these the mother was 42 years old. One affected fetus had a score of 1 and the other four had scores of 2 or greater. Using a genetic sonogram scoring index of 1 or greater (age not considered), five of eight fetuses with Down syndrome (62.5%) were identified, as well as 150 of 1030 (14.6%) of normals. Down syndrome was undetected in three fetuses of 1030 (1 in 343) or 0.29%. In addition, when all women 40 years old or older underwent karyotype testing regardless of their sonographic findings, six of eight Down syndrome fetuses were identified (75%), as well as 271 of 1030 (26.3%) of normals. The number of cases of Down syndrome not detected was two in 1030 (1 in 515) or 0.19%. In conclusion, the genetic sonogram scoring index was used to identify approximately 75% of fetuses with Down syndrome, with amniocentesis being recommended in 26.7% of a high-risk population.