Prenatal screening for trisomy 21: a comparative performance and cost analysis of different screening strategies.

BACKGROUND: Prenatal screening for chromosome aneuploidies have constantly been evolving, especially with the introduction of cell-free fetal DNA (cfDNA) screening in the most recent years. This study compares the performance, costs and timing of test results of three cfDNA screening implementation strategies: contingent, reflex and primary. METHODS: We modelled enhanced first trimester screening (eFTS) as the first-tier test in contingent or reflex strategies. cfDNA test was performed contingent on or reflex from eFTS results. A comparison was made between cfDNA screening using sequencing technology and Rolling Circle Amplification (RCA)/imaging solution. All model assumptions were based on results from previous publications or information from the Ontario prenatal screening population. RESULTS: At an eFTS risk cut-off of ≥1/1000, contingent and reflex cfDNA screening have the same detection rate (DR) (94%) for trisomy 21. Reflex cfDNA screening using RCA/Imaging solution provided the lowest false positive rate and cost. The number of women requiring genetic counselling and diagnostic testing was significantly reduced and women received their cfDNA screening result 9 days sooner compared with the contingent model. While primary cfDNA screening improved the trisomy 21 DR by 3-5%, it was more costly and more women required diagnostic testing. CONCLUSION: Reflex cfDNA screening is the most cost-effective prenatal screening strategy. It can improve the efficiency of prenatal aneuploidy screening by reducing the number of patient visits and providing more timely results.

First trimester ultrasound assessment for fetal aneuploidy.

Screening tests for trisomy 21 have gradually become more refined and now involve complex statistical models that combine demographic, biophysical, and biochemical parameters to produce individualized risk estimates for pregnant women. An understanding of the evolution of the principles, methods, and statistical techniques applied to Down syndrome screening is valuable as these processes can be transferred to other, more prevalent, adverse pregnancy outcomes. First trimester ultrasound forms the foundation of this process.

Formative assessment based on an audit and feedback improves nuchal translucency ultrasound image quality.

OBJECTIVES: The purpose of this work was to study the impact of an audit and feedback on the quality of routine first-trimester nuchal transparency ultrasound images. METHODS: Eighty-eight sonographers were each sent 2 different series of 30 consecutive nuchal translucency images at a mean interval of 3 months to a dedicated, protected server for remote double-blind independent analysis based on the new Collège Français d'Echographie Foetale/Centre National de la Recherche Scientifique image-scoring method (https://www.cfef.org/evaluation/ISMCFEFCNRS.pdf). The sonographers were classified as low (score below the median) or high (score above the median) scorers for each series. Before their second evaluation, 73 of the 88 sonographers received a feedback report on their first series of images, whereas the other 15 participants received no feedback. The baseline characteristics of the participants who did and did not receive feedback were comparable. RESULTS: Participants who received feedback increased their average score significantly, from a mean ± SD of 11.1 ± 1.3 to 13.4 ± 1.4 among low scorers (P < .00001) and from 15.1 ± 1.2 to 16.0 ± 1.4 among high scorers (P < .001), whereas no significant change was seen among participants who received no feedback (low scorers, 10.9 ± 1.5 to 12.1 ± 2.0; P = .11; high scorers, 14.7 ± 1.3 to 14.6 ± 1.3; P = .99). The proportion of satisfactory images increased by 48% among low scorers who received feedback. CONCLUSIONS: Formative assessment based on a moderately intensive audit and feedback is feasible and effective for improving the quality of routine first-trimester nuchal transparency ultrasound images.

Utilization of available prenatal screening and diagnosis: effects of the California screen program.

OBJECTIVE: In 2009, the California Genetic Disease Branch introduced an aneuploidy screening program allowing Medi-Cal (state insured) patients access to state-sponsored first-trimester screening. The objective of this study was to assess the effect of greater access to prenatal screening on available resources at a single center. STUDY DESIGN: Data of prenatal screening and diagnostic procedures performed 4 months before the introduction of the program were compared with those of 12 months following the introduction. RESULT: Between December 2008 and March 2010, 7689 women underwent first trimester screening, 1286 underwent amniocentesis and 398 underwent chorionic villus sampling. When a comparison was made between the 4 months before and the 12 months after the program's introduction, a greater number of nuchal translucency (NT) examinations was seen to have been performed (384 per month vs 513 per month, P=0.001). Prenatal diagnostic procedures did not increase, but a greater proportion was performed for positive screen results. CONCLUSION: Introduction of the California screening program was associated with increased NT procedures and fewer invasive procedures for advanced maternal age.

Genetic assessment following increased nuchal translucency and normal karyotype.

OBJECTIVE: The objective of this study was to assess the first formal approach for monitoring genetic/developmental syndromes associated with the presence of an increased nuchal translucency (NT) thickness (>3 mm) in the first trimester of pregnancy. METHODS: Multiple technologies-a DNA chip using the APEX technology, qPCR, microfluidic PCR, and sequencing-were applied to assay 310 mutations across five conditions-Noonan syndrome, congenital adrenal hyperplasia, spinal muscular atrophy (SMA), DiGeorge syndrome, and Smith-Lemli Opitz syndrome. RESULTS: We report the results of assessing the first 120 patients in which 8 cases of Noonan syndrome were detected as well as an unusually high rate of heterozygosity for SMA. CONCLUSION: While testing for Noonan syndrome in association with increased NT appears warranted, the reported association of the remaining four genetic syndromes is likely to be weak and possibly insignificant.

Assessment of nuchal translucency thickness and the fetal anatomy in the first trimester of pregnancy by two- and three-dimensional ultrasonography: a pilot study.

AIM: To evaluate the use of three-dimensional ultrasonography (3D) as an alternative for examining fetal anatomy and nuchal translucency (NT) in the 1(st) trimester of pregnancy. METHOD: Prospective study of 199 low risk pregnant women undergoing 1(st) trimester ultrasound scan for fetal anomalies. The NT and fetal anatomy were evaluated by three-dimensional (3D) ultrasonography after the standard two-dimensional (2D) examination. The gold standard in this study was the 2D ultrasonography. RESULTS: In some of the evaluated parameters the 3D method approaches the conventional 2D results. These parameters are the crown-rump length (CRL), the skull - brain anatomy (93.5%), the spine (85.4%), the upper (88.4%) and lower limbs (87.9%) and the examination of the fetal abdomen (98.5%). Some of the anatomic parameters under evaluation revealed a statistically significant difference in favor of the 2D examination. During the 3D examination the nasal bone was identified in 62.1% of the cases, the stomach in 85.9%, and the urinary bladder in 57.3% of the cases. The NT was assessed accurately in half of the cases compared to 2D examination. CONCLUSION: The 3D ultrasound is insufficient for the detailed fetal anatomy examination during the 1(st) trimester of pregnancy. Nevertheless, the method might be improved in order to be considered as a screening method.

Assessment of sonographer nuchal translucency measurement performance--central tendency and dispersion.

OBJECTIVE: To assess center and sonographer nuchal translucency (NT) measurements that were performed as part of routine prenatal screening for Down syndrome. METHODS: Sonographers were assessed for measures of central tendency and dispersion by comparing them with expected population median and dispersion parameters. NT measurements were converted to multiples of the expected NT values according to CRL (NTMoM) and transformed to their log(10) equivalent (log(10) NTMoM). Central tendency and measurement were assessed by checking whether the median of the NTMoM distribution and SD of the log(10) NTMoM distributions were, respectively, within 5% or 10% of the expected median of 1 and SD of 0.1. Assessment was performed using both the Center specific and Fetal Medicine Foundation (FMF) reference NT for Crown rump length (CRL). RESULTS: The median NT MoM was 0.95 MoM using the FMF reference and 1.01 MoM when assessed using our center specific reference median. The difference between the center and FMF derived NT MoMs was statistically significantly (p < 0.0001). NTMoM medians increased over time at a rate of 0.0099 MoM per year while log(10) NT MoM measurement dispersement was similar to the 0.1 value expected and decreased by 0.0048 per year. CONCLUSION: Centers should routinely monitor the quality of NT measurements used to estimate Down syndrome screening risk and should provide individualized feedback to sonographers of their measures of central tendency and dispersion to ensure consistent and improved performance. NT reference medians adopted from other populations should be assessed and validated against a centers own measurement distribution.

Screening for twin-twin transfusion syndrome at 11-14 weeks of pregnancy: the key role of ductus venosus blood flow assessment.

OBJECTIVES: A discrepancy in crown-rump length (CRL) and/or nuchal translucency thickness (NT) between monochorionic twins has been found to be associated with an increased risk of twin-twin transfusion syndrome (TTTS). As one of the most plausible mechanisms for increased NT is hemodynamic imbalance and cardiac dysfunction, indirectly manifested by abnormal blood flow in the ductus venosus (DV), we aimed to clarify the role of DV blood flow assessment in identifying those monochorionic twins more prone to develop TTTS. METHODS: We present 99 cases of monochorionic diamniotic twin pregnancies in which CRL, NT and DV blood flow were evaluated at 11-14 weeks' gestation. RESULTS: Discrepant values of CRL were not predictive of TTTS development. Intertwin NT discrepancy >or= 0.6 mm had a sensitivity of 50.0% and a specificity of 92.0%. The presence of at least one abnormal blood flow waveform in the DV was associated with a relative risk for developing TTTS of 11.86 (95% CI, 3.05-57.45), with a sensitivity of 75.0% and a specificity of 92.0%. The combination of abnormal DV blood flow with NT discrepancy >or= 0.6 mm yielded a relative risk for the development of TTTS of 21 (95% CI, 5.47-98.33). CONCLUSIONS: Both intertwin discrepancy in NT and abnormal flow in the DV in monochorionic twins may represent early manifestations of hemodynamic imbalance between donor and recipient. In these pregnancies, in addition to NT measurement at 11-14 weeks, the Doppler assessment of DV blood flow significantly increases the performance of screening for those at risk of developing TTTS.

Assessment of intracranial translucency (IT) in the detection of spina bifida at the 11-13-week scan.

OBJECTIVE: Prenatal diagnosis of open spina bifida is carried out by ultrasound examination in the second trimester of pregnancy. The diagnosis is suspected by the presence of a 'lemon-shaped' head and a 'banana-shaped' cerebellum, thought to be consequences of caudal displacement of the hindbrain. The aim of the study was to determine whether in fetuses with spina bifida this displacement of the brain is evident from the first trimester of pregnancy. METHODS: In women undergoing routine ultrasound examination at 11-13 weeks' gestation as part of screening for chromosomal abnormalities, a mid-sagittal view of the fetal face was obtained to measure nuchal translucency thickness and assess the nasal bone. In this view the fourth ventricle, which presents as an intracranial translucency (IT) between the brain stem and choroid plexus, is easily visible. We measured the anteroposterior diameter of the fourth ventricle in 200 normal fetuses and in four fetuses with spina bifida. RESULTS: In the normal fetuses the fourth ventricle was always visible and the median anteroposterior diameter increased from 1.5 mm at a crown-rump length (CRL) of 45 mm to 2.5 mm at a CRL of 84 mm. In the four fetuses with spina bifida the ventricle was compressed by the caudally displaced hindbrain and no IT could be seen. CONCLUSION: The mid-sagittal view of the face as routinely used in screening for chromosomal defects can also be used for early detection of open spina bifida.

First-trimester risk assessment for trisomies 21 and 18 in twin pregnancy.

OBJECTIVE: Our objective was to describe performance of first-trimester combined risk assessment in twin pregnancies. STUDY DESIGN: Twin pregnancies that underwent risk assessment in our ultrasound unit from 2003-2006 were included. Adjusted risks for trisomies 21 and 18 that were based on age, nuchal translucency (NT), and biochemistry were provided for each twin. Detection rates for Down syndrome and trisomy 18 were calculated for age/NT, and age/NT/biochemistry at a screen-positive rate of 5% of pregnancies. RESULTS: Five hundred thirty-five pregnancies were included. Median maternal age was 34 years, with 47% of women > or = 35 years old. There were 7 fetuses in 6 dichorionic pregnancies with Down syndrome and 3 fetuses in 3 pregnancies with trisomy 18. For a 5% false-positive rate, age/NT identified 83.3% of Down syndrome and 66.7% of Trisomy 18 pregnancies. Adding biochemistry resulted in 100% detection rates for both conditions. CONCLUSION: The addition of biochemistry may enhance first-trimester risk assessment in twin pregnancies. Further studies with larger numbers of affected pregnancies are needed.

Nuchal translucency measurements for first-trimester screening: the 'price' of inaccuracy.

OBJECTIVE: First-trimester aneuploidy screening is in transition from the phase of 'development' to that of 'diffusion.' As with all other technologies, there is risk of diminished performance until newer centers are well experienced. Typically, inexperienced sonographers under-measure nuchal translucency (NT), and experience, training and continual monitoring of data are needed to ensure that measurements do not deviate. Here we assess the impact of systematic under-measurement on abnormality detection. STUDY DESIGN: Actual NT measurements from 13,887 normal fetuses, 82 with trisomy 21 (T21) and 61 with other abnormalities (OA) with birth outcome data were mathematically modified to show either a 25% or 0.5-mm decrease in measurement. The impact upon sensitivity and screen-positive rates were assessed. RESULTS: Reducing the NT measurements of T21 and OA cases lowers the sensitivity from 81.7 and 70.5%, respectively, to 67.1 and 62.3% (p < 0.01). If normals are correspondingly lowered, then the screen-positive rates are reduced from 6.9 to 2.0 and 2.5%. To maintain the same screen-positive rates and sensitivity, the risk threshold would have to be increased from 1/300 to 1/556. CONCLUSION: Minor inaccuracies in NT measurements as small as 25% or 0.5 mm will have very significant negative impacts upon abnormality detection, reducing detection rates by 18% (81.7 to 67.1%). Just as it is completely accepted that laboratory measurements require standardization and quality assurance, NT measurements, because they are used in an algorithm, need to be treated with the same rigor. That way the published data from centers that have developed such screening can be applied by other operators at other sites when counseling their patients.

Nuchal translucency measurement in first trimester Down syndrome screening.

(1) Approximately three in every four fetuses with Down syndrome have increased nuchal translucency (NT), which is a larger than normal build-up of fluid at the back of the neck. (2) The ultrasound measurement of NT between 11 and 14 weeks' gestation, in combination with the mother's age and the levels of placental biochemical markers in her blood, can be used to detect approximately 84% of fetuses with Down syndrome. (3) The accuracy of NT measurement is affected by fetal position, measurement technique, the type of risk-calculation software used, and the sonographer's experience and technical expertise. (4) A rigorous standardization and quality assurance system for NT measurement is needed before any test using NT ultrasound is offered universally. The cost of establishing such a program is unknown.

Comparison of first and second trimester aneuploidy risk assessment.

Counseling regarding the options for aneuploidy risk assessment is complicated and requires thorough counseling with the patient. Second trimester serum risk assessment has been the gold standard because of widespread availability, low cost, and vast experience with counseling and performance. First trimester risk assessment is becoming more widely available and provides increased sensitivity for Down syndrome detection with a detection rate of approximately 87% (95% confidence interval: 84.0% to 89.4%), at a fixed false-positive rate of 5%. With the advent of first trimester techniques, controversy has arisen as there are advocates for the different recently available approaches. In this chapter, we outline the various options in a manner that will provide practical information for physicians offering such testing. Clearly, implementation of first trimester risk assessment requires special training and meticulous quality control standards for nuchal translucency and laboratory measurements, access to chorionic villus sampling, and also appropriate counseling regarding risk assessment options.

Ultrasonographic assessment of fetal nuchal translucency (NT) at 11th and 14th week of gestation--Polish multicentre study.

UNLABELLED: THE AIMS OF THE STUDY WERE: To evaluate range and median values of NT in a large, unselected Polish population; to determine the value of the 95th percentile and the median values for NT for given weeks of late 1st trimester pregnancy and to determine the level of chromosomal aberration risk corresponding to the values of the 95th percentile in the examined groups; to examine the possible correlation between CRL, NT width as well as the mother's age with the risk of the most frequent chromosomal aberrations. MATERIAL & METHODS: We have retrospective analyzed 7,866 pregnant women. All fetuses of this women had NT measurement performed, as well as CRL and assessed of the most frequent chromosomal abnormalities. The group of pregnant women was divided into 2 subgroups: until and above 35 years old. All population group was divided into 3 subgroups depending on gestational age (11, 12 and above 13th weeks of gestation). RESULTS: The median of NT in all population group was 1.5 mm and 95th percentile was 2.4 mm, whilst in group with low risk median of NT and 95th percentile were the same and in group with high risk of chromosomal abnormalities respectively 1.5 mm and 2.5 mm. There were strong correlations between maternal age and the risk of most frequent chromosomal abnormalities from NT. CONCLUSIONS: The obtained results of median values and the 95th percentiles of NT in the examined group and the age groups under 35 and 35 plus are similar to these quoted by FMF. The risk levels of trisomy of 21st chromosome were similar to the reference values used by FMF. With gestational age, NT value increases in a non-linear way, therefore it is incorrect to use the term "a normal value" for NT, therefore, only the risk level calculated with the dedicated software using NT and CRL measurements with maternal age should be stated.

First trimester ultrasound screening for fetal aneuploidy and middle cerebral artery Doppler assessment for fetal alloimmunization.

PURPOSE OF REVIEW: Traditional methods of fetal evaluation require invasive procedures (e.g. amniocentesis) with an inherent, albeit low, risk of complications and pregnancy loss. As medical knowledge and ultrasound technology have advanced, noninvasive modes of fetal evaluation have become increasingly used. Two disorders in which this has been most applied are fetal aneuploidy and alloimmunization to red blood cell antigens. RECENT FINDINGS: First-trimester screening protocols for fetal aneuploidy combine ultrasound measurement of the fetal nuchal translucency with the measurement of two maternal serum hormones, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A. This combination detects approximately 85% of women pregnant with fetuses with trisomy 21. An increase in the velocity of fetal middle cerebral artery blood flow occurs in the setting of moderate to severe fetal anemia and can be measured with Doppler ultrasound. Middle cerebral artery evaluation is equally sensitive in the prediction of anemia as amniocentesis for bilirubin breakdown products and has less associated risk. It has an additional benefit because it can also be applied to causes of anemia other than hemolysis. SUMMARY: Noninvasive methods of fetal assessment are becoming increasingly commonplace. There has been a dramatic decrease in the use of prenatal diagnostic services as screening strategies have become available. Doppler assessment of the velocity of blood flow through the fetal middle cerebral artery will allow for more judicious application of invasive procedures to pregnancies at significant risk for anemia.