R. Bahado-Singh

An 8‐Center Study to Evaluate the Utility of Midterm Genetic Sonograms Among High‐Risk Pregnancies

Objective. A multicenter study was undertaken to evaluate the diagnostic efficacy of a genetic sonogram. Methods. Eight centers provided data on 176 pregnancies complicated by fetal Down syndrome. One hundred thirty‐four pregnancies were considered high risk because of advanced maternal age (>35 years), and 42 were considered high risk for having “abnormal” triple‐screen results (risk >1:250). Each center provided fetal biometric data, information regarding the presence or absence of major structural abnormalities, and between 3 and 6 additional ultrasonographic markers for trisomy 21. The heterogeneity of our 8 independent “sensitivity estimates” was evaluated by Poisson regression, and a single combined estimate of the sensitivity was calculated. Results. Of the total 176 cases of trisomy 21, 125 fetuses (71.0%) had either an abnormal long bone length (femur length, humerus length, or both), a major structural abnormality, or a Down syndrome marker. The combined diagnostic sensitivity was 71.6%, with a range of 63.6% (7 of 11) to 80% (8 of 10). Five centers had sensitivity estimates falling between 64% and 76%. The sensitivity of individual markers varied between 3% (sandal gap) and 46.5% (nuchal skin fold thickness). A condensed regimen of nuchal skin fold thickness, femur length, and a standard anatomic survey would screen in 56.8% of fetuses with Down syndrome. Conclusions. This 8‐center study that included many fetuses with Down syndrome validates the concept that the genetic sonogram can be used to better adjust the Down syndrome risk for high‐risk patients.

New Down syndrome screening algorithm: ultrasonographic biometry and multiple serum markers combined with maternal age.

OBJECTIVE We compared the Down syndrome screening efficiency of a new algorithm that combines humerus length measurement and serum analytes versus that of the traditional triple-analyte serum screen. STUDY DESIGN Humerus length measurements were obtained prospectively in 1743 midtrimester (14 to 24 weeks) singleton fetuses before genetic amniocentesis. All patients had triple-marker serum screening before amniocentesis. Data on humerus length were expressed as multiples of the median, and were normalized by log transformation. Backward multiple stepwise logistic regression analysis was performed to determine which combination of biometry and serum markers best predicted fetal Down syndrome. The screening efficiency of the traditional triple-analyte algorithm was compared with that of a new multivariate gaussian algorithm that combined biometry and serum markers. RESULTS There were 31 (1.8%) fetuses with Down syndrome in the study population. In the regression analysis humerus length, human chorionic gonadotropin, alpha-fetoprotein, and maternal age were significant predictors of Down syndrome, but unconjugated estriol was not. The combined algorithm (humerus length, human chorionic gonadotropin, and alpha-fetoprotein and age) was superior to the traditional triple screen for Down syndrome detection. The sensitivities at fixed false-positive rates were consistently higher in the combination than in the triple-screen protocol. For example, at a 10% false-positive rate the sensitivities were 65.0% and 52.3%, respectively. Similarly, at a 15% false-positive rate the sensitivities were 73.5% and 55.0%, respectively. CONCLUSION A new screening algorithm combining humerus length and serum analytes was superior to the traditional triple screen. Although we used a high-risk population in this study, it is expected that the observed superiority of the combination screen would persist in a population of younger women. The development of a combined biometric and serum analyte screening algorithm for estimating individual odds could represent an advance in prenatal Down syndrome screening.

Risk of Down syndrome and any clinically significant chromosome defect in pregnancies with abnormal triple-screen and normal targeted ultrasonographic results

OBJECTIVE Our purpose was to study prospectively the use of ultrasonographic biometry to refine the risk estimates for both Down syndrome and any clinically significant chromosome defect in women with abnormal biochemical triple-screen results. STUDY DESIGN Ultrasonographic biometry and anatomic survey were performed on study and control cases. Expected values for humerus, femur, combined humerus plus femur lengths, and abdominal circumference were generated on the basis of biparietal diameter obtained from a normal group. Threshold observed/expected values of each measurement for screening for Down syndrome and clinically significant chromosome defects were determined with receiver-operator characteristic curves. By stepwise logistic regression analysis the optimal screening parameters, including nuchal thickness, for detection of Down syndrome and clinically significant chromosome defect were determined. Risk tables for chromosome anomalies were developed on the basis of ultrasonography and triple-screen values. RESULTS Of 1034 cases at risk for Down syndrome (risk > or = 1/270) or trisomy 18 on the basis of triple-screen results, there were 11 cases of Down syndrome, 1 of trisomy 18, and 17 clinically significant chromosome defects. Abnormal nuchal thickness or observed/expected humerus length < 0.92 was the most sensitive parameter for Down syndrome detection. Abnormal nuchal thickness or observed/expected combined femur and humerus length < 0.90 was the most sensitive for significant chromosome defects. With abnormal biometry or anatomy the Down syndrome risk was 8 of 127 versus 1 of 753 in normals, odds ratio 50.4 (95% confidence interval 6.4 to 90.2), p < 0.00001, and the risk of significant defects was 11 of 90 versus 6 of 830 in normals, odds ratio 19.3 (95% confidence interval 6.4 to 60.5), p < 0.00001. In a pregnancy with a 1 in 270 triple-screen risk for Down syndrome, normal biometric and anatomic results reduce the risk to 1 in 2100. CONCLUSION Normal ultrasonographic anatomy and biometry significantly reduces the risk of both Down syndrome and any significant chromosome defects in pregnancies with abnormal triple-screen results.

A new splenic artery Doppler velocimetric index for prediction of severe fetal anemia associated with Rh alloimmunization.

OBJECTIVE We developed a new Doppler index for the noninvasive prediction of severe fetal anemia by means of Doppler velocimetry of the main splenic artery. STUDY DESIGN Doppler velocimetry of the main splenic artery was performed in 85 healthy fetuses and in 22 nonhydropic study case patients (41 measurements) at risk for anemia from Rh sensitization. The deceleration angle between the line describing the average slope during the diastolic phase of the cycle and the vertical axis was measured and expressed in multiples of the median (MoM) for gestational age. Severe anemia was defined as a hemoglobin deficit (mean hemoglobin for gestational age minus measured hemoglobin) >/=5 g/dL. Anemia overall was defined as a hemoglobin deficit >/=2 g/dL. RESULTS Mean gestational age at cordocentesis was 28.6 weeks. Severe anemia was noted on 7 occasions (12.6%) and anemia was noted on 21 (51.2%) occasions. There was a significant correlation between deceleration angle and hemoglobin deficit >/=2 g/dL (r = 0.5763, P <.0001) and also with hemoglobin deficit >/=5 g/dL (r = 0.6418, P <.0001). At deceleration angles <0. 90 MoM, a 90.5% sensitivity and a 30% false-positive rate were achieved for anemia detection. At a threshold deceleration angle of <0.60 MoM, the sensitivity for severe anemia was 100%, with an 8.8% false-positive rate. CONCLUSION We report a new and sensitive Doppler velocimetric technique for predicting severe anemia. By means of splenic artery velocimetry, all cases of severe anemia could be identified before the development of hydrops, with a >91% reduction in the rate of cordocentesis.

Combined ultrasound biometry, serum markers and age for Down syndrome risk estimation

Objective To compare Down syndrome screening efficiency of the standard serum triple analyte screen to that of a four‐component screen consisting of ultrasound biometry and serum markers in the second trimester.

Splenic artery Doppler peak systolic velocity predicts severe fetal anemia in rhesus disease.

OBJECTIVE We sought to determine whether main splenic artery Doppler peak systolic velocity predicts severe anemia in the rhesus-alloimmunized fetus. STUDY DESIGN Splenic artery Doppler peak systolic velocity was obtained before cordocentesis in rhesus-alloimmunized fetuses. Normative values for mean peak systolic velocity based on gestational age were obtained cross-sectionally from a separate group of 144 normal fetuses. The peak systolic velocity values in the study group were expressed as multiples of the median for gestation, and threshold values were used as a screening test for severe anemia. The hemoglobin deficit was defined as mean hemoglobin for gestation minus measured hemoglobin. A hemoglobin deficit value of > or =5 g/dL was used to define severe anemia. We used the peak systolic velocity to screen for severe anemia in the overall study group and the subgroups with or without prior transfusions. RESULTS The study population consisted of 26 singleton nonhydropic fetuses in which cordocentesis and Doppler measurements were performed on a total of 55 occasions. The mean gestational age and standard deviation at cordocentesis was 29.6 +/- 4.0 weeks. Severe anemia was noted in 20% of fetal cord blood specimens obtained. On the basis of a receiver operating characteristic curve, a peak systolic velocity of > or =1.4 multiples of the median had a detection rate of 100%, with a false-positive rate of 20.8% in the subgroup with no prior transfusion (relative risk, 4.8; 95% confidence interval, 2.2-10.5). For peak systolic velocity threshold of > or =1.50 multiples of the median, corresponding values in the group with one prior transfusion were 80% and 12.5%, respectively (relative risk, 2.5; 95% confidence interval, 1.2-5.3). There was no risk of severe anemia with a peak systolic velocity below the median for gestation. CONCLUSION Fetal hydrops is rare, with a hemoglobin deficit of <5 g/dL. In the first such report the main splenic artery peak systolic velocity was noted to be a strong predictor of severe anemia. For the overall population, all such instances could be diagnosed while cordocentesis was performed 22.7% of the time. There is no risk of severe anemia with Doppler peak systolic velocities below the median for gestational age. The measurement is easily obtained and should be investigated as a clinical tool for minimizing the necessity for cordocentesis.

The genetic sonogram in screening for Down syndrome: response to the JAMA study.

Assistance was provided by Alfred Z. Abuhamad, MD, Beryl R. Benacerraf, MD, Dru E. Carlson, MD, Joshua A. Copel, MD, Greggory R. DeVore, MD, Harris J. Finberg, MD, Lyndon M. Hill, MD, David A. Nyberg, MD, Wayne H. Persutte, BS, RDMS, Lawrence D. Platt, MD, Manuel Porto, MD, Ilan Timor-Tritsch, MD, Anthony M. Vintzileos, MD, and Douglas Wilson, MD. n the February 28, 2001, issue of JAMA, an article appeared by Smith-Bindman et al1 entitled, “SecondTrimester Ultrasound to Detect Fetuses With Down Syndrome: A Meta-analysis.” The authors summarized 59 prospective and retrospective studies from the literature in which there were data on ultrasonographic markers for Down syndrome (DS), such as choroid plexus cyst, nuchal skin fold thickness (NSFT), echogenic intracardiac focus, echogenic bowel, and renal pyelectasis. In addition, the biometric measurements, humeral and femur length, were evaluated. Structural abnormalities were excluded from the analysis. Only those studies with complete ascertainment of outcome were included in the study. On the basis of rigorous criteria, data were available for analysis of 1930 pregnancies affected by fetal DS and 130,363 unaffected pregnancies. The authors reported an average age among all patients in the meta-analysis of 34 years, and 88% of the studies were performed on women at increased risk of chromosomal abnormalities because of advanced maternal age, abnormal serum test results, or family history of chromosomal abnormalities. The best performer was nuchal skin fold thickness, which had a positive likelihood ratio of 17. However, the authors calculated that, despite this large 17-fold increase in risk, “15,893 average-risk patients and 6818 high-risk patients would require screening for each case of fetal DS identified.” Also, they concluded that the rest of the DS markers were of such low yield in isolation that they had only “marginal impact on the risk of DS.” Last, because the markers were detected in only a small number of affected fetuses, the authors concluded that the likelihood of DS did not decrease substantially after normal examination findings.

Nuchal thickness, urine β-core fragment level, and maternal age for Down syndrome screening

OBJECTIVE Our purpose was to report the midtrimester Down syndrome screening efficiency of a 2-analyte algorithm, urine beta-core fragment (a metabolite of human chorionic gonadotropin) and nuchal thickness, along with maternal age in a high-risk population undergoing genetic amniocentesis. METHOD Nuchal thickness, humerus length, and maternal urine beta-core fragment levels were measured prospectively before genetic amniocentesis in 1360 singleton pregnancies, 21 (1.5%) of which had fetal Down syndrome. All analyte levels were expressed as multiples of the normal medians based on biparietal diameter. Backward-stepwise logistic regression was used to determine whether the markers were significant independent predictors of fetal Down syndrome. Matrix analysis was used to calculate an adjusted Down syndrome likelihood ratio for each patient based on the significant screening markers. Multiplication by age-related midtrimester risk gave the adjusted Down syndrome risk. The sensitivity and false-positive rates at different Down syndrome screening thresholds were used to generate a receiver-operator characteristics curve. The area under the curve was used to assess the value of this screening test. RESULTS On the basis of logistic regression, beta-core fragment level (P 1/60 the sensitivity and false-positive rate for Down syndrome were 85.7% and 4.9%, respectively, when beta-core fragment level, nuchal thickness, and maternal age were used. Correspondence screening values at a risk threshold > 1/150 were 95.2% and 10.8%, respectively. The area under the receiver-operator characteristics curve was 0.9357 (SE = 0. 0137), indicating that the algorithm is excellent for Down syndrome screening. CONCLUSION In this study, a combination algorithm consisting of nuchal thickness, urine beta-core fragment level, and maternal age had a high screening efficiency for Down syndrome. This algorithm should be investigated as a new option for women at high risk of having a fetus with Down syndrome.