Pitfalls of ultrasonographic yolk sac measurement.

PURPOSE: Novel aneuploidy screening has been suggested for measuring the yolk sac during very early pregnancy. However, in a pilot study the measured diameters differed up to 29 % from the overall average. The aim of this study was to analyze the impact of image magnification on yolk sac measurement. MATERIALS AND METHODS: From November 3, 2009 to July 28, 2010, 119 yolk sac measurements were performed. During each examination, each yolk sac was examined once with standard image magnification and once by live scan zoom. RESULTS: The measurement values were 5 % smaller in the standard image. The mean relative ratio (RR), median RR, and standard deviation (SD) were 0.951, 0.950, and 0.103 mm, respectively (95 % CI 0.744 to 1.158 mm). Regarding absolute differences, the mean, median, and standard deviation were -0.222 mm, -0.220 mm, and 0.473 mm, respectively, (95 % CI -1.169 to + 0.725 mm). With standard zoom (magnified images), the SD was 1.142 mm (1.099 mm). CONCLUSION: Five criteria should be regarded for optimal image settings: image magnification during live scan, optimal gain setting, enhanced gamma level, median section plane, and out-to-out caliper placement.

Age-independent first trimester screening for Down syndrome: analysis of three modified software programs with 6,508 pregnancies.

BACKGROUND: The conventional first trimester screening (FTS) method integrates maternal age into risk calculation. It was suggested that this concept increases the false-positive rate in older, and the false-negative rate in younger mothers. MATERIALS AND METHODS: Six thousand five hundred and eight combined FTS with known fetal outcome underwent regular risk calculation with the software programs Pia fetal database (PIA) (GE-ViewPoint, GE Medical Systems), prenatal risk calculation (PRC) (Version 1.0.61, gmt/nexus), and JOY (Version 2.1, PET software). The results were mathematically modified as if generated with age-independent software (PIA(mod), PRC(mod), and JOY(mod)). RESULTS: 17 of 40 trisomy 21 cases were present in women younger than 35. A right shift in the mean maternal age of false-negative cases occurred in all programs (PIA: 30.00, PIA(mod): 32.00, PRC: 30.00, PRC(mod): 32.25, JOY: 30.00, JOY(mod): 34.50). The overall false-positive rate declined by -40.03% (PIA(mod)), -38.64% (PRC(mod)), and -37.50% (JOY(mod)) and in women over 35 (40) years by -72.37, -73.45, and -73.20% (-89.04, -90.33, and -90.56%), being then as high as in the other age groups. CONCLUSION: First trimester screening would become reasonable in women over 40 years. However, women over 35 would also be more often affected by false-negative results. The implications of a concept adaptation should be analyzed in a large prospective study.

[Prospective performance evaluation of first trimester screenings in Germany for risk calculation through http://www.firsttrimester.net]. / Prospektive Testleistungsbewertung des Ersttrimester Screenings in Deutschland bei Risikoberechnung über http://www.firsttrimester.net.

BACKGROUND: In 2008, 2 351 first trimester screenings were calculated by a newly developed internet database ( http:// www.firsttrimester.net ) to evaluate the risk for the presence of Down's syndrome. MATERIAL AND METHODS: All data were evaluated by the conventional first trimester screening according to Nicolaides (FTS), based on the previous JOY Software, and by the advanced first trimester screening (AFS). After receiving the feedback of the karyotype as well as the rates of the correct positives, correct negatives, false positives, false negatives, the sensitivity and specificity were calculated and compared. RESULTS: Overall 255 cases were investigated which were analysed by both methods. These included 2 cases of Down's syndrome and one case of trisomy 18. The FTS and the AFS had a sensitivity of 100%. The specificity was 88.5% for the FTS and 93.0% for the AFS. CONCLUSION: As already shown in former studies, the higher specificity of the AFS is a result of a reduction of the false positive rate (28 to 17 cases). As a consequence of the AFS with a detection rate of 100% the rate of further invasive diagnostics in pregnant women is decreased by having 39% fewer positive tested women.

Analysis of the distribution shift of detected aneuploidies by age independent first trimester screening.

INTRODUCTION: First trimester screening (FTS) became standard in non-invasive testing for chromosomal abnormalities in early pregnancy. The individual risk is calculated on the basis of a general background risk, which refers to the maternal age. A new method, Advanced Firsttrimester Screening (AFS) excludes the background risk in its algorithm. This study had the aim to analyze how the detection of aneuploidies is influenced by the in- or exclusion of the maternal age in the risk calculation. MATERIALS AND METHODS: The data of 15,228 first trimester screenings were recalculated with FTS and AFS. The study cohort was divided by age into nine groups and the numbers of detected cases were recorded according to the groups of age. RESULTS: Of 129 detected aneuploidies 90% got the same test results, disregarding whether risk assessment is performed including maternal age or not. FTS detected five aneuploidies at age 35 or older that were not recorded by AFS. AFS detected six aneuploidies that were not detected by FTS. Out of these, the oldest mother was 32 years old. DISCUSSION: When excluding the maternal age from risk calculation, the detection of aneuploidies showed a shift from older to younger women. Overall, the detection rate did not change significantly. However, the false positive rate was 25% lower with the exclusion of maternal age.

Comparison of Prenatal Risk Calculation (PRC) with PIA Fetal Database software in first-trimester screening for fetal aneuploidy.

OBJECTIVES: In February 2007 new software, Prenatal Risk Calculation (PRC), for calculating the risk of fetal aneuploidy was introduced in Germany. Our aim was to investigate its test performance and compare it with that of the PIA Fetal Database (PIA) software developed and used by The Fetal Medicine Foundation. METHODS: Between 31 August 1999 and 30 June 2004 at the Women's Hospital of the Medical University of Hanover in Germany, 3120 singleton pregnancies underwent combined first-trimester screening at 11 + 0 to 13 + 6 weeks of gestation. Calculation of risk for fetal aneuploidy was computed prospectively using the PIA software. In a subsequent retrospective analysis, we recalculated risks for the 2653 of these datasets with known fetal outcome using the PRC software and compared the results. RESULTS: Of the 2653 datasets analyzed, 17 were cases of aneuploidy. At a cut-off of 1 : 230, for the detection of fetal aneuploidy, the respective sensitivity, false-positive rate and positive predictive value were 70.6%, 4.1% and 9.9% for PRC and 76.5%, 2.9% and 14.6% for PIA. At a cut-off of 1 : 300, the equivalent values were 70.6%, 5.6% and 7.5% for PRC and 76.5%, 4.0% and 11.0% for PIA. The differences in test performance between the two types of software were highly significant (P < 0.0001). DISCUSSION: The test performance of PRC was inferior to that of PIA, the sensitivity for detection of fetal aneuploidy being lower and the false-positive rate higher. Had PRC been employed prospectively in our study, 40% more women examined would have been offered unnecessarily an invasive procedure for fetal karyotyping.

[Three-dimensional scatter plot analysis to estimate the risk of foetal aneuloidy]. / Dreidimensionale scatterplotanalyse zur risikoeinschätzung für fetale aneuploidien.

PURPOSE: First trimester screening (FTS) according to Nicolaides is now a worldwide established method for prenatal aneuloidy screening. An improvement was achieved by the "Advanced First Trimester Screening" (AFS). It was the aim of the current study to set up scatter plots from nuchal translucency (NT), Papp-A and fbeta-hCG, to derive likelihood ratios therefrom and to apply them to a test collective. We wanted to examine whether or nor the test performance of FTS could further be improved. MATERIAL AND METHODS: In a multicentre study 10 136 singleton pregnancies were recruited. Risk assessment for the presence of aneuploidies was performed by the Pia Fetal Database (PIA). In addition, all data were recalculated by the AFS module of the online platform www.firsttrimester.net . In a third step, a newly developed algorithm was utilised, in which the foetal parameters DeltaNT, Papp-A and fbeta-hCG were put into a three-dimensional scatter plot. The surrounding volume was segmentally divided and for each space the relation of the healthy to the affected foetuses found therein was determined. Furthermore, for all participiants of this study, the likelihood ratios were examinied at the segment according to the currently measured values. This method is designated as AFS-3D. RESULTS: Within the observed fetuses, 86 cases with aneuploidy were detected. By appropriate choice of the cut-off the sensitivities were found to be 83 % (PIA and AFS) and 82 % (AFS-3D), respectively, and do not differ significantly from each other. The specificity could be improved from 94 % (PIA) to 96 % (AFS) and was further advanced to 98 % by the AFS-3D method. At the same time the false positive rate was lowered from 654 (PIA) to 397 (AFS) and 228 (AFS-3D) cases, respectively. DISCUSSION: By means of the new AFS-3D method the same count of diseased fetuses was detected compared with prior screening tests. Simultaneously, expectant mothers were spared from unnecessary invasive diagnostics in 65 % of the cases. The choice of an altered cut-off or other volume shapes are feasible and should be examined in further studies.

Using "Degree of Extremeness" instead of "Multiples of Median" in first trimester risk assessment for Down syndrome-an improved method or just a gimmick in face of political motivations?

INTRODUCTION: The concept of first trimester Down syndrome screening based on (NT) nuchal translucency measurement was introduced by the Fetal Medicine Foundation (FMF), London, in the late 1990s. For Germany, the mandate of NT training and auditing was assigned to the newly established German branch of the FMF in 2002. In January 2007, following the organisational split between FMF London and FMF Germany, the FMF Germany released its own, novel calculation software ("Prenatal risk calculation", PRC), for this field. It is the aim of this study to compare the modified biochemical calculation method based on "Degree of Extremeness" (DoE) with the well-proven concept of "Multiple of Median" (MoM). MATERIALS AND METHODS: The fbeta-hCG and PAPP-A values of 266 first trimester examinations were categorised by gestational age, nicotine consumption and body weight. For each, a scatter plot and Pearson correlation was derived. As a second step, only patients with no nicotine consumption and a body weight between 55 and 65 kg were considered. The remaining 84 cases were again classified by gestational age and a statistical analysis was performed. RESULTS: The correlation of the DoEs with the respective MoM values was found to be quite good (r = 0.76, P < 0.01). After dividing the population by gestational age, the cohort of early pregnancies showed a steeper fss-hCG correlation curve than later stages. The examination regarding nicotine consumption showed no significant differences between smokers and non-smokers. In contrast, maternal body weight was found to have a marked influence. When only body weights between 55 and 65 kg were included and smokers were excluded, the Pearson correlations clearly converged. DISCUSSION: In this study, the utilisation of DoEs instead of MoMs was not clearly superior but it also did not seem to be inappropriate. However, it is most problematic to ignore evidently meaningful factors like body weight and ethnicity. It must also be considered risky to introduce a new calculation software to the market, when it is not clear whether the test performance is in fact comparable to established software concepts, especially in view of the fact that not only a new (unproven) database, but also a new (again unproven) algorithm is used in the PRC software. As the new program has not been evaluated yet, the test performance parameters should be validated urgently.

[The prenatal detection of trisomy 13, 18, and 21: comparison of the advanced first trimester screening (AFS) with the first trimester screening according to Nicolaides]. / Die pränatale Detektion der Trisomien 13, 18 und 21: Vergleich des Advanced First Trimester Screenings (AFS) mit dem Ersttrimester-Screening nach Nicolaides.

PURPOSE: As a defined basic risk, the maternal background risk represents the most important influencing factor in the First Trimester Screening according to Nicolaides. However, the generated risk estimations often deviate from the observed clinical-practical values. The aims of this study were to perform a test performance analysis of the first trimester screening according to Nicolaides and its comparison with the novel "Advanced First Trimester Screening (AFS)" algorithm, which explicitly excludes the maternal background risk. MATERIAL AND METHODS: At the Medical University of Hannover 2 743 pregnancies at 11 + 0 to 13 + 6 weeks of gestation underwent a combined ultrasonographic and biochemical First Trimester Screening. In a prospective approach, the risk calculation according to Nicolaides was performed with both the classic and the specific algorithm of the "ViewPoint-PIA Fetal database (PIA)" software. The risk calculation with the AFS algorithm was carried out in a retrospective approach. RESULTS: The observed study population included seven cases of trisomy 21, two cases of trisomy 18, and one case of trisomy 13. Both the PIA and the AFS algorithm reached a sensitivity of 80 %, a false negative rate of 20 %, and a negative prediction value of 99.9 %. However, with a specificity of 97.01 %, a false positive rate of 2.99 %, and a positive prediction value of 11.76 % the AFS algorithm showed a better test performance than the PIA algorithm (96.06 %, 3.94 %, and 9.20 % respectively). CONCLUSIONS: The calculation with AFS generated more precise risk estimations for trisomy 13, 18, and 21. An examination in large, prospective studies may be recommended to consider an introduction of this novel test strategy.