Serum Urine And Ultrasound Screening Study Research Articles

Distribution of Nuchal Translucency in Antenatal Screening for Down's Syndrome

ObjectiveTo determine whether the standard deviation of nuchal translucency (NT) measurements has decreased over time and if so to revise the estimate and assess the effect of revising the estimate of the standard deviation on the performance of antenatal screening for Down's syndrome.SettingData from a routine antenatal screening programme for Down's syndrome comprising 106 affected and 22,640 unaffected pregnancies.MethodsNT measurements were converted into multiple of the median (MoM) values and standard deviations of log10 MoM values were calculated in affected and unaffected pregnancies. The screening performance of the Combined and Integrated tests (that include NT measurement) were compared using previous and revised estimates of the standard deviation.ResultsThe standard deviation of NT in unaffected pregnancies has reduced over time (from 1998 to 2008) (e.g. from 0.1329 to 0.1105 [log10 MoM] at 12–13 completed weeks of pregnancy, reducing the variance by about 30%). This was not observed in affected pregnancies. Compared with results from the serum, urine and ultrasound screening study (SURUSS), use of the revised NT standard deviations in unaffected pregnancies resulted in an approximate 20% decrease in the false-positive rate for a given detection rate; for example, from 2.1% to 1.7% (a 19% reduction) at a 90% detection rate using the Integrated test with first trimester markers measured at 11 completed weeks' gestation and from 4.4% to 3.5% (a 20% reduction) at an 85% detection rate using the Combined test at 11 completed weeks.ConclusionsThe standard deviation of NT has declined over time and using the revised estimates improves the screening performance of tests that incorporate an NT measurement.

Ductus Venosus Pulsatility Index as an Antenatal Screening Marker for Down'S Syndrome: Use with the Combined and Integrated Tests

To assess the value of ductus venosus blood flow (expressed as pulsatility index, DVPI) in antenatal Down's syndrome screening when used with the Combined and Integrated tests. DVPI measurements between 10 and 13 weeks' gestation in 66 Down's syndrome and 7184 unaffected pregnancies were collected from women attending the Hospital Clinic, Barcelona, for antenatal care from 1999 to 2007 and combined with the Serum Urine and Ultrasound Screening Study (SURUSS) data to model screening performance, safety and cost-effectiveness of the screening tests with and without DVPI. The median DVPI multiple of the normal median in Down's syndrome pregnancies was 1.55 (95% CI 1.36-1.73). As a single screening marker without using maternal age, DVPI has a 62% detection rate for a 5% false-positive rate. At a 90% detection rate (first trimester measurements at 11 weeks' gestation) the addition of DVPI reduced the false-positive rate of the Combined test from 8.5% to 4.6% and the Integrated test from 2.0% to 1.1%, with a corresponding reduction in fetal losses from diagnostic procedures. There was no material loss of cost-effectiveness. Addition of DVPI measurements to the Combined and Integrated tests substantially improves the efficacy and safety of antenatal Down's syndrome screening.

Evaluation of four years of prenatal screening for aneuploidies in Hospital S. Francisco Xavier using the integrated test

We report an audit of our Prenatal Screening Programme for aneuploidies between March 2003 and August 2007. Overall detection and false positive rates were 86% and 3.6%, respectively. These results are similar to those predicted by the Serum, Urine and Ultrasound Screening Study (SURUSS).

Antenatal screening for Down's syndrome using the Integrated test at two London hospitals

We carried out an audit of antenatal screening for Down's syndrome using the Integrated test (which provides a single screening result from information collected in the late first and early second trimesters of pregnancy) which was introduced into routine antenatal care at two London hospitals, University College Hospital (UCH) and St Mary's Hospital, in 2003-4. The audit was based on 15,888 women who accepted screening and booked in the first trimester. The Down's syndrome detection rate was 87% (95% confidence interval [CI], 74-95) consistent with an expected detection rate of 89% based on applying the estimates of screening performance of the Serum, Urine and Ultrasound Screening Study (SURUSS) to the maternal age distribution of women who were screened at UCH and St Mary's. The observed false-positive rate was 2.1% (95% CI, 1.9-2.3), compared with an expected of 2.5% for women of the same age. An audit trail (conducted at UCH) indicated that 98% (10,746/10,961) of women accepted integrated screening (2% having a first trimester test) and of these, 94% (10,116) completed both stages of the test. The audit demonstrated that it is feasible to conduct integrated screening within the NHS with a high acceptance rate and a screening performance consistent with that determined from previous research studies.

Comparison of different strategies in prenatal screening for Down’s syndrome: cost effectiveness analysis of computer simulation

Objectives To assess and compare the cost effectiveness of three different strategies for prenatal screening for Down’s syndrome (integrated test, sequential screening, and contingent screenings) and to determine the most...

Prenatal screening for serious congenital heart defects using nuchal translucency: a meta‐analysis

To assess the performance of nuchal translucency (NT) measurements in screening for congenital heart defects (CHD) which would benefit from prenatal detection. A literature search was conducted of studies published prior to August 2007 of CHD and NT measurements in fetuses without chromosome defects. From this, data on 159 pregnancies were obtained. Fetuses with CHD that would benefit from prenatal detection were identified and their NT measurements were compared with NT measurements in 29 776 unaffected fetuses without Down syndrome from the Serum Urine and Ultrasound Screening Study (SURUSS) trial to determine the screening performance of NT measurements. In all 67 fetuses with CHD were identified as potentially likely to benefit from prenatal detection. Using NT measurements, the estimated detection rate (DR) for a 5% false-positive rate (FPR) was 52% (95% CI: 42-71). Prenatal screening for CHD using NT measurements is likely to be effective, and given that NT measurement is already in place as part of prenatal screening for Down syndrome; this is an ideal time to set up demonstration projects to validate these results.

Combined test + inhibin A at week 13 in contingent sequential testing: an interesting alternative for first‐trimester prenatal screening for Down Syndrome

To analyze various possibilities of using dimeric inhibin A (DIA) as a first-trimester marker, during week 13, for diverse sequential strategies together with the combined test (CT) [which uses pregnancy-associated plasma protein A, free beta-human chorionic gonadotrophin and nuchal translucency]. We analyzed three sequential strategies (nondisclosure, stepwise and contingent) for measuring DIA in week 13. Multivariate Gaussian modelling was used to estimate second-trimester, false-positive and detection rates. Model parameters were taken from the Serum, Urine and Ultrasound Screening Study (SURUSS) assay. The three sequential strategies provided high and comparable levels of effectiveness, with false-positive rate for fixed detection rate of 85% and detection rate for fixed false-positive rate of 5% values of about 91 and 2%, respectively. The contingent strategy (with two CT risk cutoffs, of 1 in 50 and 1 in 2000) produced a screening-positive rate of 0.8% with CT, while only 23% of the women needed subsequent DIA measurement. First-trimester sequential screening using CT together with DIA measurement in week 13 is capable of producing results that are comparable with those of the integrated test, with the additional advantage that the final result is obtained earlier. It is recommended that this strategy be evaluated in large-scale prospective studies.

Single large study or meta-analysis parameters: choosing the most appropriate tool for Down syndrome screening in the first trimester

The aim of the present study is to determine whether the use of population parameters derived from meta-analysis produces better test characteristics in the first-trimester combined screening than those obtained from large single studies, when screening for Down syndrome (DS) in singleton pregnancies. Retrospective analysis was done on a database of 4248 singleton pregnancies, including 13 cases of DS, for which the values of three markers used in the combined first-trimester test were available. The risk of DS was calculated for each mother from the different population parameters derived by meta-analysis or from two large single studies: the Fetal Medicine Foundation study (FMF) and the Serum, Urine and Ultrasound Screening Study (SURUSS). When the detection rate was fixed at about 85%, the false-positive rate was significantly higher (Chi-square = 53.49, p < 0.0001) when the parameters obtained by the meta-analysis (6.25%) were compared with the two single studies (FMF, 4.15% and SURUSS, 3.75%). This study highlights the importance of selecting appropriate population parameters when insufficient DS cases are available in the study population. When screening for DS in singleton pregnancies during the first trimester, the use of population parameters derived from single large studies produced better test characteristics.

Sequential and contingent prenatal screening for Down syndrome

To compare the Integrated test in three policies for prenatal Down syndrome screening: Integrated screening for all women, sequential screening (first-trimester tests allowing early completion of screening for high-risk pregnancies), and Contingent screening (early completion of screening for high- and low-risk pregnancies). Estimation of detection rates (DRs) and false-positive rates (FPRs) using Monte Carlo simulation and cost effectiveness for each method. Down syndrome affected and unaffected pregnancies studied in the Serum Urine and Ultrasound Screening Study (SURUSS). RESULTS AND MAIN OUTCOMES: Integrated screening has the best screening performance. The performance of the other two policies approached that of Integrated screening as the first-trimester test FPR decreased. If the first-trimester FPR is set to 0.5% (risk >or= 1 in 30) with an overall DR of 90%, sequential and contingent screening yield overall FPRs of 2.25% and 2.42%, respectively, and 66% of the affected pregnancies are detected by the first-trimester test. The Integrated test on all women yields an FPR of 2.15%. With sequential screening, 99.5% of women would proceed to an Integrated test, or 30% with contingent screening if those with first-trimester test risks of <or=1 in 2000 are classified screen-negative and receive no further testing. About 20% of affected pregnancies identified in the first trimester using sequential or contingent screening would have unnecessary terminations (they would miscarry before the early second trimester). Contingent screening is the most cost-effective if there is no alphafetoprotein screening for neural tube defects, otherwise Integrated screening is more cost-effective. Integrated screening for all women is the simplest, most effective, and the safest policy. Contingent screening is the most complex with the lowest screening performance. Making an earlier diagnosis with sequential and contingent screening has adverse consequences that are sufficient to discourage their use.

Cross‐trimester marker ratios in prenatal screening for Down syndrome

To examine the performance of Integrated Down syndrome screening (first- and second-trimester measurements integrated into a single screening test) when ratios of the levels of the same serum markers measured in both these trimesters (cross-trimester ratios) are added as new screening markers. Using data from Serum Urine and Ultrasound Screening Study (SURUSS), second-trimester concentrations (in multiples of the median, or MoM) of pregnancy associated plasma protein A (PAPP-A), alphafetoprotein (AFP), unconjugated oestriol (uE(3)), human chorionic gonadotrophin (hCG) (free beta and total), and inhibin-A were divided by the first-trimester concentration to obtain a cross-trimester (CT) ratio for each analyte in 74 Down syndrome and 492 unaffected pregnancies. We identified CT ratios that improved screening performance and then, using Monte Carlo simulations, estimated the efficacy and cost effectiveness of adding them to the Integrated and serum Integrated tests. All the median CT ratios differed significantly between Down syndrome and unaffected pregnancies. Setting the Integrated test to achieve a 90% detection rate, the false-positive rate (FPR) was 0.7% with CT ratios for PAPP-A, uE(3), inhibin-A, and total hCG compared with 2.2% without CT ratios, a reduction of about two-thirds. Using the serum Integrated test to achieve the same 90% detection rate and the first-trimester measurements made at 11 completed weeks of pregnancy, the corresponding FPRs were 2.4 and 8.1%, a similar proportional reduction. The AFP CT ratio had little effect on screening performance. Using CT ratios did not increase the cost per Down syndrome pregnancy detected. The addition of CT ratios to an Integrated test substantially improves the efficacy and safety of prenatal screening for Down syndrome. It is cost effective and could be usefully introduced into screening programmes.

An update on antenatal screening for Down’s syndrome and specific implications for assisted reproduction pregnancies

Since the introduction of antenatal serum screening for Down's syndrome (DS) more than two decades ago, several screening approaches have been utilized in routine clinical practice. The current DS screening strategies involve mid-trimester serum biochemistry tests, first trimester tests combining sonographic markers and serum biochemistry and integration of first and second trimester markers. In this review, we evaluate the performance of DS screening strategies according to the Serum, Urine and Ultrasound Screening Study (SURUSS), the First and Second Trimester Evaluation of Risks (FASTER) Trial and the Serum Biochemistry and Fetal Nuchal Translucency Screening (BUN) Study. We also evaluate the performance of first trimester screening in studies and meta-analyses by other groups. Specific issues related to assisted reproduction technology (ART) pregnancies are also addressed in this review.

Nuchal Translucency and First-Trimester Screening

irst-trimester screening for Down syndrome has become a commonly used approach in prenatal genetic diagnosis. The drive behind the development of earlier, reliable methods of genetic screening and risk assessment is the ability to provide the parents with more options at an earlier gestational age. Currently, this involves the sonographic evaluation of fetal nuchal translucency (NT) in combination with maternal serum levels of free beta-hCG and PAPP-A to provide a risk assessment for Down syndrome.1 This is referred to as combined first-trimester screening. Based on a survey of US maternal-fetal medicine specialists in 2001, of the 543 respondents, 46% used NT sonography and 27% used first-trimester maternal serum screening for Down syndrome.3 The term "nuchal translucency" refers to the fluid-filled space between the back of the fetal neck and the overlying skin.4 It has been noted that fetuses with Down syndrome, as well as other forms of aneuploidy, have increased edema in this area, resulting in an increased NT measurement.4 Based on seminal work by Nicolaides and others, measurement ofNT in fetuses between 11 and 14 weeks has been used since the early 1990's to provide earlier risk assessment of fetuses with aneuploidy.5 Initial results indicated detection rates comparable to second-trimester maternal serum screening.' However, three recent large trials, including the US-based Firstand SecondTrimester Evaluation of Risk (FASTER) trial, the North American-based First Trimester Maternal Serum Biochemistry and Ultrasound Fetal Nuchal Translucency Screening (BUN) Study, and the European-based Serum, Urine, and Ultrasound Screening Study (SURUSS) Trial have demonstrated that combined screening in the first trimester outperforms both NT and first-trimester serum screening when performed separately, with detection rates for Down syndrome ranging from 79%87% at a false positive rate of 5% 6 This compares favorably with performance of second-trimester serum screening, also referred to as the "quad" screen, which utilizes maternal serum levels of unconjugated estriol, free human chorionic gonadotropin, alpha-fetoprotein, and inhibin A, with a detection rate of 81%.7 Furthermore, the detection rate for trisomy 18 with the combined screen was comparable to the quad screen.8 There are still a number of issues which limit the use ofNT. The technical expertise required to obtain reliable and reproducible images has proven challenging. Furthermore, patients must have access to providers who are capable of performing first-trimester chorionic villus sampling when a patient screens positive. There is still no consensus as to the most efficient or

Second-trimester Down's syndrome serum screening: double, triple or quadruple marker testing?

The recommendations of the UK National Screening Committee (NSC) are based on the findings of the Serum, Urine and Ultrasound Screening Study (SURUSS). Our study sought to establish if the SURUSS findings, in terms of detection rates (DR) and false-positive rates (FPR) for various second-trimester marker combinations, could be replicated in a local setting. We investigated the effects of adding inhibin-A and unconjugated oestriol to our existing double test protocol. This retrospective study examined 1000 control pregnancies and 128 affected pregnancies. The inhibin-A method was associated with considerable assay drift and very marked within-batch imprecision (intrabatch percent coefficient of variation [CV] = 17%). At a cut-off of 1 in 250, the quadruple test showed a DR of 72%, the triple test 70% and the double test 63%. There were no significant differences between the FPRs for any of the combinations, which were all between 6.6% and 7.0% for a 1 in 250 cut-off. In our view, the current inhibin-A assay is unacceptable as a screening marker due to poor assay performance. We have reviewed the NSC benchmark programme outcomes, and would suggest that the 2005 target of a DR of at least 60% with an FPR of less than 5% is achievable using triple testing in the second trimester in conjunction with universal scan dating. Our results suggest that the April 2007 target of a DR of 75% with an FPR of less than 3% is unachievable using current second-trimester maternal serum screening.

SURUSS in Perspective ‡

Until the publication of the Serum Urine and Ultrasound Screening Study (SURUSS) report, it was difficult to compare the different antenatal screening tests for Down's Syndrome because of variations in study designs. We here present the main results from SURUSS, updated to take account of recent information on nuchal translucency in Down's Syndrome pregnancies, and discuss their implications. SURUSS was a prospective study of 47,053 singleton pregnancies (including 101 pregnancies with Down's Syndrome) conducted in 25 maternity units. Nuchal translucency measurements were taken. Serum and urine samples collected between 9 and 13 weeks, and again between 14 and 20 weeks of pregnancy were stored. Samples from each affected pregnancy and five matched controls were tested for currently used or suggested biochemical Down's Syndrome screening markers. Pregnancies were followed up to determine the presence or absence of Down's Syndrome. For an 85% Down's Syndrome detection rate, the false-positive rate for the Integrated test (nuchal translucency and pregnancy associated plasma protein-A [PAPP-A] at 11 completed weeks of pregnancy, and alpha-fetoprotein, unconjugated oestriol [uE3], free beta or total human chorionic gonadotrophin (hCG) and inhibin-A in the early second trimester) was 0.9%, the Serum integrated test (without nuchal translucency) 2.7%, the Combined test (nuchal translucency with free beta-hCG and PAPP-A at 11 weeks) 4.3%, the Quadruple test (alpha-fetoprotein, uE3, free beta or total hCG and inhibin-A) 6.2%, and nuchal translucency at 11 weeks, 15.2%. All tests included maternal age. Using the Integrated test at an 85% detection rate, there would be six diagnostic procedure-related unaffected fetal losses following amniocentesis per 100,000 women screened compared with 35 using the Combined test or 45 with the Quadruple test. The Integrated test offers the most effective and safe method of screening for women who attend in the first trimester. The next best test is the Serum integrated test. The Quadruple test is the best test for women who first attend in the second trimester. There is no justification for retaining the Double (alpha-fetoprotein and hCG) or Triple (alpha-fetoprotein, uE3, and hCG) tests, or nuchal translucency alone (with or without maternal age) in antenatal screening for Down's Syndrome.

SURUSS in perspective.

Until the publication of the Serum Urine and Ultrasound Screening Study (SURUSS) report, it was difficult to compare the different antenatal screening tests for Down's Syndrome because of variations in study designs. We here present the main results from SURUSS, updated to take account of recent information on nuchal translucency in Down's Syndrome pregnancies, and discuss their implications. SURUSS was a prospective study of 47,053 singleton pregnancies (including 101 pregnancies with Down's Syndrome) conducted in 25 maternity units. Nuchal translucency measurements were taken. Serum and urine samples collected between 9 and 13 weeks, and again between 14 and 20 weeks of pregnancy were stored. Samples from each affected pregnancy and five matched controls were tested for currently used or suggested biochemical Down's Syndrome screening markers. Pregnancies were followed up to determine the presence or absence of Down's Syndrome. For an 85% Down's Syndrome detection rate, the false-positive rate for the Integrated test (nuchal translucency and pregnancy associated plasma protein-A [PAPP-A] at 11 completed weeks of pregnancy, and alpha-fetoprotein, unconjugated oestriol [uE(3)], free beta or total human chorionic gondaotrophin (hCG) and inhibin-A in the early second trimester) was 0.9%, the Serum integrated test (without nuchal translucency) 2.7%, the Combined test (nuchal translucency with free beta-hCG and PAPP-A at 11 weeks) 4.3%, the Quadruple test (alpha-fetoprotein, uE(3), free beta or total hCG and inhibin-A) 6.2%, and nuchal translucency at 11 weeks, 15.2%. All tests included maternal age. Using the Integrated test at an 85% detection rate, there would be six diagnostic procedure-related unaffected fetal losses following amniocentesis per 100,000 women screened compared with 35 using the Combined test or 45 with the Quadruple test. The Integrated test offers the most effective and safe method of screening for women who attend in the first trimester. The next best test is the Serum integrated test. The Quadruple test is the best test for women who first attend in the second trimester. There is no justification for retaining the Double (alpha-fetoprotein and hCG) or Triple (alpha-fetoprotein, uE(3), and hCG) tests, or nuchal translucency alone (with or without maternal age) in antenatal screening for Down's Syndrome.

First and Second Trimester Antenatal Screening for Down's Syndrome: The Results of the Serum, Urine and Ultrasound Screening Study (SURUSS)

First and Second Trimester Antenatal Screening for Down's Syndrome: The Results of the Serum, Urine and Ultrasound Screening Study (SURUSS)

First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

The matching criteria were gestation (using an ultrasound crown–rump length or biparietal diameter measurement), duration of storage, and centre. Screening performance of the individual markers and combinations of markers together with maternal age was assessed using standard methods. In addition pairs of first and second trimester serum samples from 600 controls were tested to secure a larger set in which screening performance could be deter­ mined using distribution parameters based on dates (time since first day of the last menstrual period).