O. Deren

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.

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.

Gestational age standardized nuchal thickness values for estimating mid-trimester Down's syndrome risk.

OBJECTIVE Our aim was to develop gestational age standardized indices of fetal nuchal thickening. In addition, we wanted to develop a method for combining nuchal thickness data with maternal age for calculating individual Downs syndrome risk. METHODS Nuchal thickness was measured prospectively in pregnancies undergoing genetic amniocentesis. A regression equation for expected median nuchal thickness based on the biparietal diameter (BPD) was developed. Nuchal thickness values were expressed as multiples of the median (MoM). Additionally, a new parameter, percentage increase in nuchal thickness (PIN) (measured minus expected nuchal thickness) X100/expected nuchal thickness, was used. Receiver operator characteristics curves for Downs syndrome detection based on nuchal thickness values expressed as MoM, PIN, and in mm were compared. Log10 transformation of MoM data resulted in a Gaussian distribution, and the Downs syndrome likelihood ratios were calculated based on the heights of the Gaussian curves. Likelihood ratios were also calculated based on PIN values. The screening efficiency of maternal age alone was compared to age plus MoM, and age plus PIN values by multiplying age-related risk by the likelihood ratio corresponding to the given nuchal thickness MoM or PIN values. RESULTS There were 3,574 chromosomally normal and 50 Downs syndrome fetuses in the study. Both PIN and MoM values for nuchal thickness were closely correlated (R = 1.00, P<0.001) and each was poorly correlated with gestational age (R = 0.018, P = 0.28). The Downs syndrome screening efficiency of PIN, MoM, and nuchal thickness values in mm were not significantly different. The addition of nuchal thickness data to maternal age-related risk significantly improved the Downs syndrome screening efficiency: Area under the ROC curve for maternal age risk = 0.58, maternal age + PIN area = 0.79 (P<0.001 compared to maternal age alone) and for maternal age + MoM = 0.77 (P<0.005 compared to maternal age alone). CONCLUSIONS The development of gestational age standardized nuchal thickness indices makes it possible to combine ultrasound and maternal age-related risk to derive individual Downs syndrome odds.