First-trimester Combined Screening Research Articles

First‐trimester combined screening for trisomy 21 with different combinations of placental growth factor, free β‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A

To examine placental growth factor (PlGF) in euploid and trisomy 21 pregnancies at 11-13 weeks' gestation and to model the impact on first-trimester combined screening. PlGF was measured in 509 (409 euploid and 100 trisomic) fetal serum samples derived from prospective first-trimester combined screening for trisomy 21 at 11-13 weeks' gestation. The serum samples were stored at -80°C, following the measurement of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) levels, for median time spans of 0.9 and 4.1 years in the euploid and trisomy 21 pregnancies, respectively. The effect of additional PlGF measurement at the time of combined screening was investigated by simulating fetal nuchal translucency (NT) measurements and multiples of the median (MoM) values for PAPP-A, free β-hCG and PlGF for 20,000 euploid and 20,000 trisomy 21 pregnancies. Patient-specific combined risks were calculated based on maternal age and fetal NT in addition to free β-hCG, PAPP-A and PlGF, PAPP-A and PlGF or free β-hCG and PlGF, and detection and false-positive rates were calculated. Median PlGF-MoM was 1.0 (95% confidence interval (CI), 0.96-1.04) in euploid fetuses and significantly lower, at 0.73 (95% CI, 0.70-0.76), in trisomy-21 fetuses (P < 0.0001). There was no significant dependency between PlGF-MoM and either gestational age at the time of blood sampling (r = 0.087, P = 0.392) or sample storage time (r = 0.028, P = 0.785). Modeled detection and false-positive rates for first-trimester combined screening (based on maternal and gestational age, fetal NT and maternal serum biochemistry) without PlGF were 85% and 2.7% for a fixed risk cut-off of 1:100. The addition of PlGF increased the detection rate to 87% and reduced the false-positive rate to 2.6%. Screening by maternal age and fetal NT in combination with PlGF and PAPP-A or in combination with PlGF and free β-hCG provided detection rates of 82% and 79%, with false-positive rates of 2.7% and 3.0%, respectively. In pregnancies with trisomy 21 PlGF is reduced. The impact on the overall screening performance for trisomy 21 is low and does not justify the measurement of PlGF solely for trisomy 21 screening. However, as PlGF is measured with the aim of assessing the risk for pre-eclampsia, further improvement in screening for trisomy 21 can be considered as an added benefit.

First trimester combined screening for Down′s Syndrome with NT, Free-βhCG and PAPP-A

Objective To explore the sensitivity of using NT, combined with serum biochemical markers (Free-βhCG，PAPP-A) for Down′s Syndrome screening in early stage of pregnancy. Methods Collect pregnant women aged 17-45 years old voluntary antenatal screening in our hospital from March 2009 to October 2010, a total of 11882 cases.Serum Free-βhCG and PAPP-A were measured NT value was determined by ultrasound at 11-13w+6d of gestation.Calculating combined screening (NT, Free-βhCG, PAPP-A), and serum integrated screening (Free-beta hCG, PAPP-A) risk, respectively, using the risk calculation software for the same person. Results Early pregnancy screening was performed in 11 882 patients, 18 had a fetus with Down′s syndrome, a rate of 0.15%.The detection rates of Down′s syndrome in combined screening and serum integrated screening were 83.3% and 72.2% respectively.The specificities were 98.4% and 97.3% and detection efficiency were 7.18%, 3.90% respectively.Areas under the curve (AUCs) of first-trimester combined screening and serum integrated screening were 0.975（95% CI:0.943,1.007）, 0.901 (95% CI:0.789, 1.013) respectively. Conclusion In early stage of pregnancy, combined screening for Down′s syndrome has higher sensitivity and specificity than serological screening, has higher detection rate in the same false-positive rate case, which can effectively reduce the pregnant women to receive invasive puncture.（Chin J Lab Med，2012,35：932-935） Key words: Pregnancy trimester; first; Down syndrome; Prenatal diagnosis; Nuchal translucency measurement

Can first-trimester screening program detect women at high risk for gestational diabetes mellitus?

This study was designed to compare first-trimester maternal serum biochemical markers of aneuploidy and fetal nuchal translucency in pregnancies complicated by gestational diabetes mellitus and those of a control group. The study included 60 gestational diabetic and 60 control women who attended the first-trimester combined screening program for Down syndrome between 11 and 14 gestational weeks with complete follow-up data and delivered in our institution. Maternal serum free β-human chorionic gonadotropin, pregnancy-associated plasma protein-A and fetal nuchal translucency were investigated. The combined risks, double test risks and age risks were calculated by PRISCA software version 4.0. Comparison of the results between the two groups yielded no significant differences in serum levels of free β-human chorionic gonadotropin and fetal nuchal translucency. However, women who developed gestational diabetes mellitus had significantly lower pregnancy-associated plasma protein-A. And also, the combined risks and double test risks calculated by PRISCA software were statistically higher in gestational diabetic women than normal pregnant women. These results suggest that differences can be seen between diabetic and healthy pregnant women in first-trimester maternal serum biochemical markers of aneuploidy.

Prospective study evaluating performance of first‐trimester combined screening for trisomy 21 using repeat sampling of maternal serum markers PAPP‐A and free β‐hCG

To prospectively evaluate the performance of first-trimester combined screening for trisomy 21 using the biochemical markers pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (free β-hCG) obtained before and at the time of the nuchal translucency (NT) scan. Three fetal medicine departments in Denmark participated in the study. Screening for trisomy 21 was set up as a two-step approach with blood sampling performed before the NT scan (early sample) and again at the time of the NT scan (late sample). PAPP-A and free β-hCG were measured on both the early and late samples. Age-standardized detection and false-positive rates for different screening protocols were calculated. We collected two blood samples in 27 pregnancies affected by trisomy 21 and in 3891 control pregnancies. The early samples were taken between gestational ages 8 + 0 and 13 + 6 weeks, and the late samples between 11 + 3 and 14 + 6 weeks. The median interval between the samples was 17 (range, 1-40) days. We found a significantly better estimated screening performance when using early sampling vs late sampling (P < 0.05). With a risk cut-off of 1 in 100, at the time of the risk assessment the estimated detection and false-positive rates when using the early sample were 91% (95% CI, 81-98%) and 1.6% (95% CI, 1.3-2.0%), respectively. For fixed false-positive rates the highest detection rates were achieved using both blood samples. When comparing early sampling vs double sampling there was no significant difference in screening performance. In combined first-trimester screening for trisomy 21, use of early sampling with measurement of PAPP-A and free β-hCG before the time of the NT scan can optimize screening performance. Using maternal serum markers obtained both before and at the time of the NT scan has the potential to further improve performance, but larger studies are needed to confirm this potential.

Unchanged prevalence of Down syndrome in the Netherlands: results from an 11‐year nationwide birth cohort

This study aims to evaluate trends in prevalence of Down syndrome (DS) births in the Netherlands over an 11-year period and how they have been affected by maternal age and introduction of prenatal screening. Nationwide data of an 11-year birth cohort (1997-2007) from the Netherlands Perinatal Registry were analyzed. First-trimester combined screening was introduced in 2002, free of charge only for women 36 years of age or older and only on patients' request. Changes in maternal age, prevalence of DS births, and rates of births at <24 weeks (legal limit for termination of pregnancy in the Netherlands) during the study period were evaluated using logistic and linear regression analyses. In total, 1,972,058 births were registered (91% of the births in 1997-2007). Mean prevalence of DS was 14.57 per 10,000 births (95% confidence interval 14.43; 14.73); 85% of DS were live births. No significant trend in overall prevalence of DS births was observed (p = 0.385), in spite of a significant increase of mean maternal age during the same period (p < 0.001). The increased prevalence of DS births at ≥ 24 weeks among women ≥ 36 years of age (p = 0.011) was offset by a significant increase in the proportion of DS births at <24 weeks among women aged <36 years (p = 0.013). The proportion of DS births in the Netherlands has not changed during the period 1997-2007.

Impact of bias in crown–rump length measurement at first‐trimester screening for trisomy 21

To assess the repeatability of crown-rump length (CRL) measurement and examine the effect of its over- and underestimation on first-trimester combined screening. Intra- and interoperator repeatability of CRL measurement at 11-13 weeks of gestation was assessed in 124 cases by two operators. Raw data were transformed into gestational age and intra- and interoperator repeatability was evaluated by within-operator standard deviation (SD) and the SD of differences in measurements between both operators. Modeling techniques were used to assess the impact of CRL measurement error on general population screening and on the operator-specific screening performance. The impact of errors in CRL measurement were investigated by simulating fetal nuchal translucency (NT) measurements and multiple of the median (MoM) values for pregnancy-associated plasma protein A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) for 500 000 euploid and 500 000 trisomy 21 pregnancies at 12 weeks and 9 weeks of gestation, and adding to or subtracting from each CRL value up to 10 mm and recalculating patient-specific risks. Within-operator SD of the CRL measurement was 1.27 days of gestation. The SD of the differences in CRL measurement between operators was 1.37 days of gestation. Both intra- and interoperator 95% limits of agreement were around ± 5 mm. In general population-based screening, a CRL measurement error SD of 5 mm accounts for an estimated 5% of the SD of log MoM PAPP-A and less than 1% of the SD of log MoM free β-hCG. Modeling the effect of removing this measurement error on overall screening performance showed a minimal impact. For a risk cut-off of 1 in 100, the benefit in terms of overall screening performance would be an increase in detection rate of about 1% and a reduction in false-positive rate of less than 0.1%. With regard to the operator-specific screening performance, a consistent 5-mm underestimation of CRL reduces the detection rate from 84% to 79% and the false-positive rate from 2.4% to 1.2%. With a consistent 5-mm overestimation the rates would be 88% and 5.6%, respectively. The impact of the interoperator variability in CRL measurement on patient-specific risk needs to be taken into account when interpreting first-trimester screening results. A systematic under- or overestimation of CRL should be avoided.

Validation of First Trimester Screening for Trisomy 21 in Singapore with Reference to Performance of Nasal Bone

Introduction: The aim of this study is to describe the performance of first trimester screening (FTS) for trisomy 21 using maternal age, serum biochemistry and fetal nuchal translucency (NT) in a single center and to evaluate the effect of nasal bone on screening performance. Material and Methods: In 12,585 singleton pregnancies, the NT and nasal bone were examined. The majority of these mothers also had their serum biochemical markers analyzed. Risk was computed using different combinations of maternal age, biochemistry, NT and nasal bone. Down syndrome cases were confirmed by karyotyping. Results: There were 12,519 normal pregnancies, 31 with trisomy 21 and 35 with other chromosomal abnormalities. Without considering the nasal bone, the combined FTS detected 87.1% of trisomy 21 fetuses (false positive rate 5.1%), using 1:300 as the risk threshold, and this was further improved to 96.8% with the policy that classifies all fetuses with an absent nasal bone as high risk. Subgroup analysis showed that the detection rate would be 90.9%, with a false positive rate of 3.7%, if nasal bone was incorporated in the risk algorithm, compared to 81.8% and a false positive rate of 5.4% if it was not used. Discussion: FTS is very effective in early detection of trisomy 21 in Singapore. The nasal bone is a useful marker that can substantially improve the screening performance.

Is the Addition of the Ductus Venosus Useful when Screening for Aneuploidy and Congenital Heart Disease in Fetuses with Normal Nuchal Translucency?

Objective: The aim of this study was to examine the possible role of Doppler ultrasound assessment of ductus venosus (DV) blood flow at 11⁺⁰–13⁺⁶ weeks’ gestation in fetuses with normal nuchal translucency (NT) in screening for autosomal trisomies (AT) and for congenital heart diseases (CHD) in chromosomally normal fetuses. Methods: First-trimester combined screening for trisomy 21 (T21) was carried out prospectively for 7 years in singleton pregnancies. NT and the pulsatility index for DV (DVPI) were calculated. The DV was analyzed according to its association with AT and CHD. The detection rate (DR), false-positive rate (FPR), positive predictive value (PPV), and odds ratio (OR) for abnormal DV were calculated. Results: Abnormal DV as an early marker of euploid CHD gives a DR of 12.5%, an FPR of 4.3%, a PPV of 1.4%, and a negative predictive value (NPV) of 99.5%, with an OR of 3.1 (95% CI 1.3–7.4). Moreover, abnormal DV as an early marker of AT shows a DR of 35.7%, an FPR of 4.3%, a PPV of 1.2%, an NPV of 99.9%, and an OR of 12.3 (95% CI 4.1–36), and the values are 33.3, 4.3, 0.97, and 99.9% and 11 (95% CI 3.2–36.9), respectively, for T21. Conclusions: Our data supports the association between increased DVPI and CHD or AT. The sensitivity of this marker is not strong enough to be used a screening test.

Association between pregnancy-associated plasma protein-A and gestational diabetes requiring insulin treatment at 11–14 weeks of gestation

Objective: To evaluate whether gestational diabetes mellitus (GDM) requiring insulin treatment (White’s classification A2) is associated with an alteration of pregnancy-associated plasma protein-A (PAPP-A) serum levels at first-trimester screening between 11 and 14 weeks of gestation. Methods: We collected data (2007–2010) of all women who developed GDM requiring insulin treatment and completed first-trimester combined screening program including the determination of serum PAPP-A and free β-human chorionic gonadotropin (β-hCG). A total of 288 women were included in this study. Each of the 72 women who developed GDM was matched with three unaffected controls. Results: Women with GDM were significantly older (34.2 ± 5.9 vs. 32.3 ± 5.5 years, P = 0.007) and delivered significantly earlier (38.40 ± 2.25 vs. 39.1 ± 2.2 gestational weeks, P = 0.01). Multiple regression analysis revealed, that PAPP-A and β-hCG were independently associated with each other (P = 0.04) but there was no association between GDM/no GDM and the first-trimester serum markers (P = 0.77). Conclusion: Our data suggest that women who are developing GDM needing insulin treatment do not have altered PAPP-A levels at 11–14 weeks.

Improved diagnostic accuracy by using secondary ultrasound markers in the first‐trimester screening for trisomies 21, 18 and 13 and Turner syndrome

The aim of this study was to examine the effectiveness of a combination of parameters at first-trimester screening for fetal aneuploidies, including ultrasound assessment of the nasal bone (NB), blood flow in the ductus venosus (DV) and flow across the tricuspid valve. Screening for aneuploidy was carried out in 4172 singleton pregnancies between January 2006 and December 2010. Diagnostic accuracy of combined screening [inclusive of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A] and of secondary ultrasound markers [NB, tricuspid regurgitation (TR) and Doppler studies of the DV] obtained at the same visit was assessed using the receiver operating characteristic (ROC) curve analysis. The individual areas under the ROC curves of NT, NB, DV or TR ranged between 0.7 and 0.8, representing acceptable discrimination. The area under the ROC curve of combined first-trimester screening was 0.87, whereas the addition of secondary ultrasound markers increased the area under the curve to 0.92, which represents excellent discrimination. At a risk cutoff of 1 : 275, the detection rate for aneuploidy increased from 87% to 92% (z statistic = 1.78, P = 0.076), and the false positive rate decreased from 5.3% to 4.8%. The addition of secondary ultrasound markers (NB, DV and TR) to combined first-trimester screening showed a tendency toward improved accuracy of the screening.

Second‐trimester soft markers: relation to first‐trimester nuchal translucency in unaffected pregnancies

Genetic sonography following first-trimester combined screening appears to increase substantially detection rates for Down syndrome but it relies on the unproved assumption of independence between these tests. In this study we aimed to investigate the relationship between first-trimester nuchal translucency (NT) and a series of second-trimester soft markers and structural defects in unaffected pregnancies. NT measurement in the first trimester was followed by second-trimester scan (18 to 23 + 6 weeks) including examination for three categorical markers (intracardiac echogenic foci, hyperechogenic bowel and structural defects) and measurement of nasal bone length, nuchal-fold thickness, femur length, humerus length, renal pelvis diameter and prenasal thickness. All continuous variables were expressed in multiples of the median (MoM) for gestation and correlation coefficients between log-transformed NT and second-trimester variables were calculated. In addition, frequencies of soft markers and structural defects in cases with increased NT were compared to those with normal NT, using MoM cut-offs. In a dataset of 1970 cases, NT was significantly correlated (P < 0.05) with all second-trimester continuous variables, the correlation being strongest for nuchal-fold thickness (r = 0.10). There was a higher frequency of cases with second-trimester nuchal-fold thickness above the 97.5(th) centile (10.7 vs. 2.2%) and hyperechogenic bowel (2.4 vs. 0.1%) in cases with increased NT. Straightforward reassessment of risk using likelihood ratios derived from the second-trimester genetic sonogram might lead to inaccurate estimates. Multivariate models using continuous second-trimester variables might be preferable in sequential screening strategies.

Maternal Serum Placental Growth Factor in Prospective Screening for Aneuploidies at 8–13 Weeks’ Gestation

Objective: To investigate whether measurement of maternal serum placental growth factor (PLGF) can improve the performance of first-trimester combined screening for trisomy-21 by fetal nuchal translucency (NT) thickness and serum free β-human chorionic gonadotropin (β-hCG) and PAPP-A. Methods: In singleton pregnancies attending for routine care, serum PLGF, free β-hCG and PAPP-A were measured at 8⁺⁰–13⁺⁶ weeks’ gestation, and fetal NT was measured at 11⁺⁰–13⁺⁶ weeks. The population included 12,154 normal and 44 trisomy-21 pregnancies. We examined the effect of adding PLGF on the performance of screening by the combined test. Results: In the trisomy-21 pregnancies the median multiple of the normal median PLGF, adjusted for gestational age, maternal weight, racial origin, smoking status and method of conception, was significantly reduced (0.6070, 95% CI 0.5543–0.6648), and this did not change significantly with gestational age. Adding PLGF to combined testing with a risk cut-off of 1 in 100 reduced the false positive rate from 2.7% (95% CI 2.5–3.0) to 2.6% (95% CI 2.4–2.8) and increased the detection rate from 85% (95% CI 75–93) to 88% (95% CI 78–95). Conclusions: Inclusion of serum PLGF improves the performance of the first-trimester combined test in screening for trisomy-21.

Screening auf Trisomie 18 und Trisomie 13 durch das kombinierte Anwenden der Risiko-Algorithmen für Trisomie 21, 18 und 13

Assessment of first-trimester combined screening for trisomy 18 and 13 with the combined use of the risk algorithms for trisomy 21, 18 and 13. First-trimester combined screening based on maternal and gestational age, fetal NT, PAPP-A and free β-hCG was assessed in 39 ,004 pregnancies. Patient-specific risks for trisomy 21, 18, 13 were computed based on the current FMF London algorithm. The study population consisted of 38 ,751 singleton pregnancies including 39 cases with trisomy 18 or 13. In the aneuploid group, median delta NT was 0.72 mm, PAPP-A was 0.21 MoM and free β-hCG was 0.33 MoM. Although only 41 % of the NT measurements of fetuses with trisomy 18 or 13 were above the 95th percentile, the detection rates for trisomy 18 or 13 were 82 % with the trisomy 18/13 algorithm and 56.4 % with the trisomy 21 algorithm. The respective false-positive rates were 0.7 % and 4.7 %. The combination of the trisomy 18/13 and the trisomy 21 algorithm with the same cut-offs led to a detection rate of 94.9 % at an overall false-positive rate of 5.0 %. Despite a substantial underestimation of the fetal NT, the combined use of the trisomy 18/13 and the trisomy 21 algorithm of the FMF London leads to a detection rate for trisomy 18/13 of about 95 % for a false-positive rate of 5.0 %.

Cribado combinado para la detección de trisomía 21 en el primer trimestre de la gestación. Impacto sobre la tasa de procedimientos invasivos de diagnóstico prenatal tras 5 años de implementación

ObjectiveTo assess the effectiveness of first-trimester combined screening in the prenatal detection of Down syndrome after 5 years of use in our hospital and its impact in reducing invasive diagnostic tests. Material and methodsThe risk of fetal chromosomal anomalies was assessed in 10,669 pregnancies with first-trimester combined screening between May 2006 and December 2010. The cut-off to indicate an invasive diagnostic test was 1/270. The amniocenteses performed between 2005 and 2010 were also analyzed. ResultsThe detection rate of screening for trisomy 21 was 90% and the false-positive rate was 3.56%. In pregnant women aged 35 years or more, the detection rate was 96.7%. In 2005 there were 496 amniocenteses. In 2010, 5 years after the introduction of screening, 148 amniocenteses were performed, representing a 70% reduction in invasive procedures. ConclusionsThe introduction of combined screening in our environment has proven effective for the detection of trisomy 21 and has substantially reduced the use of invasive prenatal diagnostic procedures. The use of advanced maternal age as an isolated criterion to indicate invasive techniques to study fetal karyotype should be questioned if high-quality universal screening is to be offered.

Resultados obstétricos en cribado combinado de las aneuploidías en el primer trimestre superior al corte con resultado de amniocentesis con cariotipo fetal normal

IntroductionTo evaluate whether there are adverse pregnancy outcomes in pregnant women with a risk index above the cut-off point in first-trimester screening for fetal chromosomal abnormalities and an amniocentesis result of normal fetal karyotype in a sample of pregnant women attending our clinic at the beginning of pregnancy. Subjects and methodsWe performed a case-control study. A series of patients who underwent first-trimester combined screening as part of antenatal care between January 2009 and January 2010 were selected. ResultsOf the maternal complications registered during the pregnancy, gestational diabetes was more frequent among cases. ConclusionsThe incidence of the remaining complications analyzed (intrauterine restricted growth, preeclampsia, oligoamnios) was similar in the two groups. In most of the pregnant women, delivery occurred after 37 weeks through the vaginal route.

Cribado combinado de síndrome de Down en primer trimestre: comparación de resultados de 4 años de aplicación con los 4 años precedentes

ObjectiveTo analyze the 4-year results of first-trimester combined screening and its impact on rates of Down syndrome detection, population coverage and invasive procedures. Subjects and methodsWe performed a retrospective population-based study over 8 consecutive years (17,564 gestations with 51 cases of Down syndrome) divided in two periods: from January 31, 2002 to January 30, 2006 without combined screening (8,182 gestations and 24 cases of Down syndrome) and from January 31, 2006 to January 30, 2010 with combined screening (8,382 gestations and 27 cases of Down syndrome). Combined screening was applied in two phases: biochemical analysis was performed in the 10th week of pregnancy and ultrasound examination in the 12th week. We compared the results of screening with the previous period based on maternal age and fetal nuchal translucency measurement. ResultsPopulation coverage was 93%. The rate of Down syndrome detection due to the application of combined screening was 89% (91% for a single fetus) with a false-positive rate of 3.5%. There were 824 invasive procedures (34.1 to diagnose one episode). During the 4 years prior to the application of combined screening, the detection rate was 71% with 1,406 invasive procedures (87.8 to diagnose one episode). ConclusionCombined screening has improved the Down syndrome detection rate by 18% and has reduced the use of invasive procedures by 41%.

Analysis of Quality of Nuchal Translucency Measurements: Its Role in Prenatal Diagnosis

Objective. Quantitative analysis of the quality of nuchal translucency (NT) measurements. Methods. First-trimester combined screening for Down syndrome was performed to all pregnant women attended in our Department from October 2003 to November 2009. NT was measured according to the Fetal Medicine Foundation (FMF) criteria by 20 trained obstetricians. The performance of NT measurements was retrospectively analyzed with regard to several quality control standards. Accuracy according to experience, professional profile, crown rump length (CRL) values, and FMF certification was statistically tested. Results. A total of 14978 NT measurements were assessed. (1) The mean operator-specific median NT-MoM values was 0,98. (2) Mean percentage of cases >95th and <5th centiles were 5,0% and 4,2%, respectively. (3) Logarithmic mean and SD of the NT MoM values were 0,00 and 0,13, respectively. (4) The DR for trisomy 21 at screening time was 90,7% for a FPR of 6,7% for standard screening strategy. (5) According to Cumulative SUM (CUSUM) figures, the performance was more acceptable in FMF-certified operators. Conclusion. Overall, quality standards show optimal NT measurements in our unit. Operator experience, a dedicated profile to fetal medicine, CRL over 60 mm, and FMF certification have a significant positive impact on the quality standards.

Contribution of “modified genetic sonography” to the combined test as a screening method for chromosomal abnormalities

Objectives: We propose to assess the contribution of “modified genetic sonography” (MGS) to the combined test (CT) as a method of stepwise sequential screening (1st step: CT, 2nd step: MGS) for chromosome abnormalities in the general population of pregnant women. Methods: Prospective study. During a 4 year study period (July 2005–June 2009) 16,548 pregnancies underwent a CT combined with MGS (major malformation and nuchal fold) as a screening method for chromosome abnormalities. We assessed sensitivity and false positive rate (FPR) (95% CI). Results: We offered a chromosome abnormalities screening test to 96.6% of pregnancies (15,995 cases). 14,160 cases are analyzed (1st step: CT, 2nd step: MGS) including 49 chromosome abnormalities and 35 Down’s syndrome (DS). The sensitivity of CT for DS was 77.1% [95% CI, 63.2–91] (27/35) and 77.5% for all chromosome abnormalities [95% CI, 65.8–89.2] (38/49) with a FPR of 4.4% [95% CI, 4.1–4.7]. If MGS was combined with CT, the sensitivity for DS was 91.4% [95% CI, 82.1–99] (32/35) and 93.8% for all chromosome abnormalities [95% CI, 87–99] (46/49) for a FPR of 5.1% [95% CI, 4.7–5.5]. Conclusions: The addition of an MGS to combined first-trimester screening test for aneuploidy improved sensitivity by 14.3% while only increasing the FPR by 0.7%.

Impact of bias in serum free beta‐human chorionic gonadotropin and pregnancy‐associated plasma protein‐A multiples of the median levels on first‐trimester screening for trisomy 21

To examine the effect of bias in median multiples of the median (MoM) levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG) on first-trimester combined screening for trisomy 21. The effects of deviations in the MoM levels of free β-hCG and PAPP-A were investigated by simulating nuchal translucency (NT) at 12 weeks and MoM values for PAPP-A and free β-hCG for 500 000 euploid and 500 000 trisomy 21 pregnancies at 9 and at 12 weeks of gestation. Likelihoods were calculated using the mixture model for NT and the standard Gaussian model for log MoM PAPP-A and free β-hCG values. Deviations in MoM marker levels were simulated by applying percentage changes of 5% to 20% to MoM values. Detection and false-positive rates were calculated with and without adjustments of the maternal serum marker levels by taking the proportion of euploid and aneuploid cases above given thresholds for each maternal age and then taking a weighted average with respect to the maternal age distribution. With median MoM levels on target, the modeled detection and false-positive rates in combined screening for trisomy 21 at 12 weeks of gestation with a fixed risk cut-off of 1 in 100 were 85% and 2.5%, respectively. For median MoM levels of free β-hCG and PAPP-A between 0.8 and 1.2 MoM, detection rates ranged from 77% to 91%, with corresponding false-positive rates ranging from 1.0% to 6.1%. In first-trimester screening for trisomy 21, biases in the serum marker MoM levels of 10% can increase false-positive rates by over 50%, whilst biases of 20% can more than double false-positive rates.

False-Negative Results in Routine Combined First-Trimester Screening for Down Syndrome in Finland

We analyzed the frequency and possible causes of false-negative (Fn) screening results in first-trimester combined Down syndrome screening in Finland. During the study period (May 1, 2002, to December 31, 2008), 76,949 voluntary women with singleton pregnancies participated in screening. Maternal age at screening, week of gestation, levels of pregnancy-associated plasma protein-A (PAPP-A), free β-human chorionic gonadotropin (fβ-hCG), and nuchal translucency (NT) measurement were compared and statistically analyzed between true-positive (Tp) and Fn cases. There were a total of 188 Down syndrome cases (1:409) in the screened population; 154 confirmed Tp and 34 Fn cases. Most Fn cases (n = 25) occurred at 12 + 0 to 13 + 6 weeks' gestation and only nine Fn cases presented between 10 and 11 weeks' gestation. According to the logistic regression analysis, the NT measurement was the most powerful discriminating factor in Fn screening results and accounted for 37.2% of Fn results. The second most important factor was fβ-hCG, adding 14.0% to R(2), followed by PAPP-A, which contributed a further 14.3%. The chosen parameters explain 83.9% of Fn results, but 16.1% remain due to unknown factor(s). All investigated parameters contributed to Fn screening results, but fetal NT was the most discriminating factor leading to an Fn screening result.