First-Trimester Risk Calculation for Trisomy 13, 18, and 21: Comparison of the Screening Efficiency between 2 Locally Developed Programs and Commercial Software

BACKGROUND Reliable individual risk calculation for trisomy (T) 13, 18, and 21 in first-trimester screening depends on good estimates of the medians for fetal nuchal translucency thickness (NT), free β-subunit of human chorionic gonadotropin (hCGβ), and pregnancy-associated plasma protein-A (PAPP-A) in maternal plasma from unaffected pregnancies. Means and SDs of these parameters in unaffected and affected pregnancies are used in the risk calculation program. Unfortunately, our commercial program for risk calculation (Astraia) did not allow use of local medians. We developed 2 alternative risk calculation programs to assess whether the screening efficacies for T13, T18, and T21 could be improved by using our locally estimated medians. METHODS We established these estimates from 19 594 women with singleton pregnancies and from 100 pregnant women carrying a fetus affected with trisomy (11 with T13, 23 with T18, and 66 with T21). All measured values were recalculated to a multiple of the median (MoM) and log10 transformed; the mean and SD were calculated for each group. RESULTS At a given risk cutoff value, we observed a slight improvement in detection rate (DR) for T13, T18, and T21 for a slightly higher false-positive rate (FPR) compared with the commercial program. The lower FPR in the commercial program was caused mainly by an inaccuracy in the PAPP-A median. CONCLUSIONS Center-specific medians for NT, hCGβ, and PAPP-A should be used in risk calculation programs to ensure high DRs and low FPRs for all 3 trisomies at a given risk cutoff.

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First-trimester presentation of ultrasound findings in trisomy 13 and validation of multiparameter ultrasound-based risk calculation models to detect trisomy 13 in the late first trimester

Journal of Perinatal Medicine ◽

10.1515/jpm-2020-0383 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Bartosz Rajs ◽

Agnieszka Nocuń ◽

Anna Matyszkiewicz ◽

Marcin Pasternok ◽

Michał Kołodziejski ◽

...

Keyword(s):

Heart Defects ◽

False Positive Rate ◽

Nasal Bone ◽

First Trimester ◽

Nuchal Translucency ◽

Trisomy 13 ◽

Ductus Venosus ◽

Patau Syndrome ◽

A Prospective Study ◽

Cns Anomalies

AbstractObjectivesTo identify the most common ultrasound patterns of markers and anomalies associated with Patau syndrome (PS), to explore the efficacy of multiparameter sonographic protocols in detecting trisomy 13 (T13) and to analyze the influence of maternal age (MA) on screening performance. Methods: The project was a prospective study based on singleton pregnancies referred for a first-trimester screening examination. The scan protocol included nuchal translucency (NT), fetal heart rate (FHR), secondary ultrasound markers [nasal bone (NB), tricuspid regurgitation (TR), ductus venosus reversed a-wave (revDV)] and major anomaly findings. Results: The study population comprised 6133 pregnancies: 6077 cases of euploidy and 56 cases of T13. Statistically significant differences were found in MA, FHR, NT, absence of NB, presence of revDV, TR and single umbilical artery. Fourteen cases of T13 (25%) demonstrated no markers of aneuploidy. The best general detection rate (DR) (DR of 78.6% with an false positive rate (FPR) of 1.2%) was obtained for a cutoff of 1/300 utilizing the “NT+T13” algorithm. The logistic regression model revealed that the central nervous system (CNS) anomalies had the greatest odds ratio (of 205.4) for T13. Conclusions: The effectiveness of the multiparameter sonographic protocol used for T13 screening showed promising results in patients older than 36 years and suboptimal results in patients between 26 and 36 years old. When screening for T13 left heart defects, CNS anomalies, abdominal anomalies, FHR above the 95th percentile, increased NT, revDV and lack of NB should receive specific attention.

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Performance characteristics of Elecsys free βhCG and PAPP-A for first trimester trisomy 21 risk assessment in gestational weeks 8+0 to 14+0

LaboratoriumsMedizin ◽

10.1515/labmed-2015-0084 ◽

2016 ◽

Vol 0 (0) ◽

Cited By ~ 1

Author(s):

Niels Tørring ◽

Carlos Aulesa ◽

Bernd Eiben ◽

Mª José Ferri ◽

Kypros H. Nicolaides ◽

...

Keyword(s):

Risk Assessment ◽

Trisomy 21 ◽

False Positive Rate ◽

Protein A ◽

First Trimester ◽

Nuchal Translucency ◽

Serological Markers ◽

Cross Sectional ◽

Positive Rate ◽

Technical Validation

AbstractScreening for fetal trisomy 21 (T21) in the first trimester includes analysis of the serological markers pregnancy-associated plasma protein A (PAPP-A) and free β-choriogonadotropin (free βhCG). With the recent launch of these assays on the cobas e and Elecsys platforms, we investigated their clinical and analytical performance.We conducted a multicenter study in 5397 pregnancies including 108 cross-sectional collected repository cases with verified fetal T21 at 8–14 weeks of gestation. A technical validation of the Roche ElecsysThe imprecision of the Elecsys free βhCG and PAPP-A assays was between 1.0% and 2.8%, and both assays showed correlation to Kryptor (free βhCG 0.981; PAPP-A 0.987), AutoDELFIA (free βhCG 0.995; PAPP-A 0.979) and IMMULITE assays (free βhCG 0.983; PAPP-A 0.983). With a cut off at 1:300 the overall sensitivity of the screening including nuchal translucency reached 94% for a 3% false positive rate.The Roche Elecsys free βhCG and PAPP-A are suitable and reliable assays for first trimester T21 risk assessment. Both assays were approved and recommended by the FMF.

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First trimester Down's syndrome screening marker values and cigarette smoking: new data and a meta-analysis on free β human chorionic gonadotophin, pregnancy-associated plasma protein-A and nuchal translucency

Journal of Medical Screening ◽

10.1258/jms.2008.008049 ◽

2008 ◽

Vol 15 (4) ◽

pp. 204-206 ◽

Cited By ~ 16

Author(s):

Jonathan P Bestwick ◽

Wayne J Huttly ◽

Nicholas J Wald

Keyword(s):

Meta Analysis ◽

False Positive Rate ◽

Protein A ◽

First Trimester ◽

Nuchal Translucency ◽

Screening Performance ◽

Combined Test ◽

Positive Rate ◽

Trimester Screening ◽

Β Hcg

Objectives To examine the effect of smoking on three first trimester screening markers for Down's syndrome that constitute the Combined test, namely nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A) and free β human chorionic gonadotophin (free β-hCG) and to use the results to determine which of these markers need to be adjusted for smoking and by how much. Methods The difference in the median multiple of the median (MoM) values in smokers compared to non-smokers was determined for NT, PAPP-A and free β-hCG in 12,517 unaffected pregnancies that had routine first trimester Combined test screening. These results were then included in a meta-analysis of published studies and the effect of adjusting for smoking on screening performance of the Combined test was estimated. Results The results using the routine screening data were similar to the summary estimates from the meta-analysis of all studies. The results from the meta-analysis were; median MoM in smokers compared to non-smokers: 1.06 NT (95% confidence interval 1.03 to 1.10), 0.81 PAPP-A (0.80 to 0.83) and 0.94 free β-hCG (0.89 to 0.99). The effect of adjusting for smoking on the Combined test is small, with an estimated less than half percentage point increase in the detection rate (the proportion of affected pregnancies with a positive result) for a 3% false-positive rate (the proportion of unaffected pregnancies with a positive result) and less than 0.2 percentage point decrease in the false-positive rate for an 85% detection rate. Conclusion Adjusting first trimester screening markers for smoking has a minimal favourable effect on screening performance, but it is simple to implement and this paper provides the adjustment factors needed if a decision is made to make such an adjustment.

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Early changes of placenta-derived messenger RNA in maternal plasma – potential value for preeclampsia prediction?

Revista Romana de Medicina de Laborator ◽

10.1515/rrlm-2015-0042 ◽

2015 ◽

Vol 23 (4) ◽

pp. 431-438

Author(s):

Sebastian Surugiu ◽

Adina Chis ◽

Codruta Mare ◽

Horea Matei ◽

Florin Stamatian

Keyword(s):

Messenger Rna ◽

False Positive Rate ◽

Protein A ◽

First Trimester ◽

Maternal Plasma ◽

Plasma Potential ◽

Multivariate Model ◽

Clinical Onset ◽

Positive Rate ◽

First Trimester Of Pregnancy

Abstract Objective: the pourpose of the study was to determine if there are any differences between placenta derived plasmatic levels of messenger RNA in normal and future preeclamptic pregnancies and if these placental transcripts can predict preeclampsia long before clinical onset Study design: we compared plasmatic expression of two placental transcripts from 12 women who ultimately developed preeclampsia with 224 controlled subjects, at the end of the first trimester of pregnancy. After multiplse-of-the-median conversion of markers we developed a multivariate model using logistic regression to determine preeclampsia risk. Results: we found lower multiples of the median values for both placental transcripts (mRNA corresponding to placental growth factor and pregnancy associated plasmatic protein A) in cases who ultimately developed preeclampsia and the multivariate model we obtained offered a preeclampsia detection rate of 75% at 10% false positive rate. Conclusion: specific early changes of placenta-derived messenger RNA could be used as preeclampsia predictors.

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Four Years' Experience With an Interlaboratory Comparison Program Involving First-Trimester Markers of Down Syndrome

Archives of Pathology & Laboratory Medicine ◽

10.5858/2009-0670-oar.1 ◽

2010 ◽

Vol 134 (11) ◽

pp. 1685-1691

Author(s):

Glenn E. Palomaki ◽

George J. Knight ◽

Geralyn Lambert-Messerlian ◽

Jacob A. Canick ◽

James E. Haddow

Keyword(s):

Down Syndrome ◽

Chorionic Gonadotropin ◽

Plasma Protein ◽

Human Chorionic Gonadotropin ◽

Interlaboratory Comparison ◽

Protein A ◽

First Trimester ◽

Nuchal Translucency ◽

Second Trimester ◽

Coefficients Of Variation

Abstract Context.—We initiated a voluntary, self-funded interlaboratory comparison program in the fall of 2005 because no proficiency testing program was available to laboratories in North America offering first-trimester, combined serum and ultrasound, Down syndrome screening. Objectives.—To evaluate the first 4 years of the interlaboratory comparison program against stated goals, to identify areas of concern, and to create new initiatives as indicated. Design.—Five serum samples are distributed 3 times a year to be tested for pregnancy-associated plasma protein A, human chorionic gonadotropin or its β subunit, and dimeric inhibin-A; participants convert these results into multiples of the median. Patient histories include nuchal translucency information that enables the calculation of the risk of Down syndrome. Also included are educational components linked to interlaboratory comparison program results. Assessment of integrated (first- and second-trimester markers) risks is accomplished by having participants combine interlaboratory comparison program results with their results from a second-trimester proficiency testing program administered by the College of American Pathologists. Results.—The precision profile for pregnancy-associated plasma protein A shows decreasing coefficients of variation with increasing pregnancy-associated plasma protein A concentrations and multiples of the median (25% to 11% and 30% to 15%, respectively). In contrast, coefficients of variation are a relatively constant 12% throughout the entire range of human chorionic gonadotropin results. On a logarithmic scale, the median coefficient of variation of the risk of Down syndrome is 9%. Conclusions.—Participants in the interlaboratory comparison program reliably measure analytes, compute multiples of the median, and calculate consistent Down syndrome risks. Assays for the measurement of pregnancy-associated plasma protein A are not standardized and are less precise than those for human chorionic gonadotropin. Participants calculate reliable median equations given sonographer-specific sets of paired crown-rump length and nuchal translucency measurements.

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Impact of Ductus Venosus Assessment in Screening Down Syndrome Protocols: An Improved Strategy in a Fetal Medicine Unit

Donald School Journal of Ultrasound in Obstetrics & Gynecology ◽

10.5005/jp-journals-10009-1010 ◽

2009 ◽

Vol 3 (2) ◽

pp. 10-17 ◽

Cited By ~ 1

Author(s):

Mónica Echevarria ◽

Carmen Comas ◽

M Angeles Rodríguez ◽

Joan Nicolau ◽

Bernat Serra ◽

...

Keyword(s):

Down Syndrome ◽

First Trimester ◽

Nuchal Translucency ◽

Serum Biochemistry ◽

Screening Strategy ◽

Maternal Serum ◽

Ductus Venosus ◽

Early Evaluation ◽

Invasive Test ◽

Screening Efficiency

ABSTRACT Objective To estimate the improvement in screening efficiency when ductus venosus (DV) Doppler studies are added to existing Down syndrome (DS) screening protocols. Methods First-trimester combined screening for trisomy 21 was prospectively carried out, from October 2003 to March 2008, in 8842 consecutive singleton pregnancies attended in our tertiary reference center. The nuchal translucency (NT) and the pulsatility index for veins for DV were calculated. The maternal serum biochemistry was measured using the Kryptor analyzer, at the same time of the scan (one step strategy) or before it (two step strategy). The detection rate (DR) and false-positive rates for standard screening strategy (maternal age, NT and biochemistry) and the same strategy but including DV assessment were calculated. Results Successful DV assessment was possible in the 95.3% of cases, representing a total of 8426 cases. Down syndrome was identified in 34 pregnancies (prevalence of DS 1:250). For a fixed screen positive rate of 5%, the addition of the DV assessment improves the DR from 85 to 94% and, for a fixed DR of 85%, it reduces the number of unnecessary invasive tests from 3.7 to 3.2%. Conclusion Early evaluation of DV can be introduced to standard DS screening strategies in experienced centers as a first level test to reduce invasive test rate derived from the existing protocols.

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INCREASED NUCHAL TRANSLUCENCY IN A FETUS WITH A NORMAL KARYOTYPE: CASE REPORT

Romanian Journal of Clinical Research ◽

10.33695/rjcr.v2i1.24 ◽

2019 ◽

Vol 2 (1) ◽

pp. 59-61

Author(s):

Cristina Moisei ◽

Anca Lesnica ◽

Romina Marina Sima ◽

Liana Pleș

Keyword(s):

Chorionic Villus ◽

Normal Karyotype ◽

First Trimester ◽

Nuchal Translucency ◽

Trisomy 18 ◽

Trisomy 13 ◽

Chorionic Villus Sampling ◽

Increased Risk ◽

First Trimester Ultrasound ◽

Increased Nuchal Translucency

Nuchal translucency (NT) is the normal fluid filled subcutaneous space measured at the back of the fetal neck measured in the late first trimester and early second trimester. Nuchal translucency screening can detect approximately 80% of fetuses with Down syndrome and other major aneuploidies with a rate of 5% of false positive results, but the merger of the NT screening with β-hCG and PAPP-A testing increases the detection rate to 90%. We present the case of a fetus with a NT of 49 mm detected at the first trimester ultrasound morphologic exam. The Kryptor test revealed a 1:35 risk for Trisomy 13 and 1:721 for Trisomy 18. We report the case of an investigated pregnancy with a NT of 49 mm detected at the first trimester ultrasound exam, with a risk of 1:35 for Trisomy 13 and 1:721 for Trisomy 18 calculated at the Kryptor test. A chorionic villus sampling was recommended and performed with a result of 46XY normal karyotype. The particularity of this case is represented by the increased nuchal translucency as well as an increased risk for trisomy 13 and 18 in a normal karyotype fetus that had a normal development in the second and third trimester with no pregnancy complications arising.

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Clinical and Economic Evaluation after Adopting Contingent Cell-Free DNA Screening for Fetal Trisomies in South Spain

Fetal Diagnosis and Therapy ◽

10.1159/000508306 ◽

2020 ◽

Vol 47 (10) ◽

pp. 749-756

Author(s):

José A. Sainz ◽

María R. Torres ◽

Ignacio Peral ◽

Reyes Granell ◽

Manuel Vargas ◽

...

Keyword(s):

False Positive Rate ◽

Cost Effective ◽

First Trimester ◽

Nuchal Translucency ◽

University Hospitals ◽

Combined Test ◽

Positive Rate ◽

Fetal Malformations ◽

Cfdna Screening ◽

Singleton Pregnancies

Introduction: Contingent cell-free (cf) DNA screening on the basis of the first-trimester combined test (FCT) results has emerged as a cost-effective strategy for screening of trisomy 21 (T21). Objectives: To assess performance, patients’ uptake, and cost of contingent cfDNA screening and to compare them with those of the established FCT. Methods: This is a prospective cohort study including all singleton pregnancies attending to their FCT for screening of T21 at 2 university hospitals in South Spain. When the FCT risk was ≥1:50, there were major fetal malformations, or the nuchal translucency was ≥3.5 mm, women were recommended invasive testing (IT); if the risk was between 1:50 and 1:270, women were recommended cfDNA testing; and for risks bellow 1:270, no further testing was recommended. Detection rate (DR), false-positive rate (FPR), patients’ uptake, and associated costs were evaluated. Results: We analyzed 10,541 women, including 46 T21 cases. DR of our contingent strategy was 89.1% (41/46) at 1.4% (146/10,541) FPR. Uptake of cfDNA testing was 91.2% (340/373), and overall IT rate was 2.0%. The total cost of our strategy was €1,462,895.7, similar to €1,446,525.7 had cfDNA testing not been available. Conclusions: Contingent cfDNA screening shows high DR, low IT rate, and high uptake at a similar cost than traditional screening.

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Impact of Including or Removing Nuchal Translucency Measurement on the Detection and False-Positive Rates of First-Trimester Down Syndrome Screening

Fetal Diagnosis and Therapy ◽

10.1159/000442198 ◽

2015 ◽

Vol 40 (3) ◽

pp. 214-218 ◽

Cited By ~ 1

Author(s):

Emmanuel Spaggiari ◽

Isabelle Czerkiewicz ◽

Corinne Sault ◽

Sophie Dreux ◽

Armelle Galland ◽

...

Keyword(s):

Down Syndrome ◽

False Positive ◽

False Positive Rate ◽

Method Comparison ◽

First Trimester ◽

Nuchal Translucency ◽

Routine Practice ◽

Detection Rates ◽

Significant Difference ◽

Positive Rate

Introduction: First-trimester Down syndrome (DS) screening combining maternal age, serum markers (pregnancy-associated plasma protein-A and beta-human chorionic gonadotropin) and nuchal translucency (NT) gives an 85% detection rate for a 5% false-positive rate. These results largely depend on quality assessment of biochemical markers and of NT. In routine practice, despite an ultrasound quality control organization, NT images can be considered inadequate. The aim of the study was to evaluate the consequences for risk calculation when NT measurement is not taken into account. Material and Method: Comparison of detection and false-positive rates of first-trimester DS screening (PerkinElmer, Turku, Finland), with and without NT, based on a retrospective study of 117,126 patients including 274 trisomy 21-affected fetuses. NT was measured by more than 3,000 certified sonographers. Results: There was no significant difference in detection rates between the two strategies including or excluding NT measurement (86.7 vs. 81.8%). However, there was a significant difference in the false-positive rates (2.23 vs. 9.97%, p < 0.001). Discussion: Sonographers should be aware that removing NT from combined first-trimester screening would result in a 5-fold increase in false-positive rate to maintain the expected detection rates. This should be an incentive for maintaining quality in NT measurement.

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Monozygotic Twins Discordant for Trisomy 13

Pediatric and Developmental Pathology ◽

10.1177/1093526616686471 ◽

2017 ◽

Vol 20 (4) ◽

pp. 340-347 ◽

Cited By ~ 7

Author(s):

Patrick McFadden ◽

Sarah Smithson ◽

Robert Massaro ◽

Jialing Huang ◽

Gail T Prado ◽

...

Keyword(s):

Uniparental Disomy ◽

Monozygotic Twins ◽

First Trimester ◽

Nuchal Translucency ◽

Trisomy 13 ◽

Ultrasound Finding ◽

Umbilical Cord Cyst ◽

First Trimester Ultrasound ◽

Mosaic Trisomy ◽

Increased Nuchal Translucency

Monozygotic twins with discordant karyotypes for trisomy 13 are rare. We report a case of a spontaneously conceived pregnancy who presented with first-trimester ultrasound finding of umbilical cord cyst and increased nuchal translucency in Twin A and no abnormalities in Twin B. Amniocentesis revealed 47,XY,+13 karyotype in Twin A and 46,XY karyotype in Twin B. Selective fetal reduction was performed for Twin A. Twin B was delivered at 32 weeks gestation with normal phenotype. Peripheral blood karyotype revealed 15% mosaicism for trisomy 13 and skin fibroblast revealed 46,XY karyotype. The surviving twin will be monitored for potential complication of uniparental disomy 13 and mosaic trisomy 13. This case reinforces the need for early ultrasound and nuchal translucency measurements, especially in twin gestations.

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