Screening Test For Down Syndrome Research Articles

Screening for trisomy 21 during the routine second‐trimester ultrasound examination in an unselected Chilean population

To evaluate the performance of a detailed ultrasound examination during the second trimester as a screening test for Down syndrome in an unselected Chilean population. This was part of an ongoing longitudinal study. Included were 3071 women with singleton pregnancies who underwent routine ultrasound examination between 21 + 0 and 25 + 6 gestational weeks as a screening test for chromosomal abnormalities and major congenital structural defects, and who were diagnosed as having trisomy 21 or being chromosomally normal. Maternal age, and eight soft markers and cardiac defects associated with Down syndrome were evaluated as a screening test using logistic regression analysis. The incidence of Down syndrome was 0.6%, and the mean maternal age was 29.4 +/- 6.2 years. At least one of four soft markers (absent nasal bone, nuchal edema, short femur, echogenic foci) and/or cardiac defects was present in 77.8% of Down syndrome fetuses and in 3.1% of normal fetuses. Furthermore, with a false-positive rate of 1%, the detection rate using the combined model of ultrasound markers and maternal age was 72.2%. Second-trimester ultrasound markers are able to detect over 70% of Down syndrome fetuses with only a 1% false-positive rate.

Molecular screening of Smith–Lemli–Opitz syndrome in pregnant women from the Czech Republic

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder. SLOS is caused by the mutations in the gene for 3beta-hydroxysterol Delta(7) reductase (DHCR7; EC 1.3.1.21), which maps to chromosome 11q12-13. DHCR7 catalyses the final step in cholesterol biosynthesis-the reduction of 7-dehydrocholesterol to cholesterol. Clinical severity ranges from mild dysmorphism to severe congenital malformation and intrauterine lethality. Pregnant women are offered a biochemical screening test for Down syndrome in the second trimester, where the suspicion for SLOS could be registered, when the unconjugated estriol (uE3) level appears low. A group of 456 fetuses with a high risk for SLOS were examined by DNA analysis. We confirmed SLOS in 5 fetuses and 11 fetuses were carriers. One novel mutation (p.G30A) was detected. The most frequently found mutations, c.964-1G > C and p.W151X, are also the most severe ones. At least one of these mutations was detected in each fetus with SLOS. This suggests that the biochemical screening of pregnant women probably uncovers mainly more severely affected fetuses. We confirmed SLOS also in two patients whose prenatal screening was negative. Both of them had nonsense mutation on one allele. It stands to reason that some modifying factors may play a role in the reduction of the uE3 level in the mother's serum.

Practical issues drawn from the implementation of the integrated test for Down syndrome screening into routine clinical practice

We have evaluated a cohort of women booked for antenatal care at University College London Hospitals. The uptake of screening was 64.4% and was significantly higher (73 versus 46%) in women who booked before 14 weeks. Of the women who booked before 14 weeks, 96.8% opted for the integrated test (IT). Overall, 5.3% failed to attend for the second blood test. The false-positive rate in the women who had the IT was 2.9%. All 11 cases of Down syndrome were detected prenatally. Our study is the first to evaluate implementation of the IT into routine clinical practice.

Women's and health professionals’ preferences for prenatal testing for Down syndrome in Australia

To describe and compare women's and health professionals' preferences for prenatal screening tests for Down syndrome. Cross-sectional questionnaire survey. Women (n = 322) attending for a glucose challenge test at 26 weeks gestation and health professionals (266 midwives and 34 obstetricians) at the Royal Women's Hospital, Melbourne, between 13 December 2002 and 30 April 2003. The relative value participants attach to attributes of Down syndrome screening tests as determined by conjoint analysis and ranking scales. Women and health professionals shared similar relative values regarding the importance of detection rate of screening tests, according to coefficients from conjoint analysis models. However, health professionals placed higher relative values on timing of prenatal tests and risk associated with the subsequent diagnostic test than did women. Comparison of coefficients suggests that, compared with health professionals, women would wait longer and accept a greater decrease in detection rate for a test if it was safer. Using the more traditional ranking scale, the safest test was ranked first by 56% of women while 47% of health professionals ranked a test with the highest detection rate first. Equal proportions ( approximately 10%) in both groups ranked the earliest test first. There is a general agreement between pregnant women and health professionals regarding the relative importance they attach to different attributes of a test. However, health professionals appeared to favour earlier timing of tests while women placed greater emphasis on safety. Utilising two different measures of preference demonstrated the complexity of decision-making.

Ultrasound Screening of Fetuses at Increased Risk for Down Syndrome: How Many Missed Diagnoses?

Certain major structural anomalies found on sonography—notably cardiac anomalies and duodenal atresia—are associated with Down syndrome (DS), and numerous “soft markers” also have been identified. As a result, some physicians and patients consider a second-trimester sonogram to be a screening test for DS. Most commonly, women who have already been identified as being at increased risk, either because of advanced maternal age or a positive serum screening test, undergo a second-trimester ultrasound examination, and only those high-risk women who also have sonographic markers of fetal DS choose amniocentesis. Alternatively, low-risk women may request an ultrasound examination as their primary screening test and forgo other screening strategies such as first- or second-trimester maternal serum screening. Most sonographic markers, however, have low positive predictive value for DS. To determine whether different sensitivities, false-positive or -negative rates, or amniocentesis-related pregnancy loss rates would make ultrasound a more effective screening tool, the investigators designed a decision analysis model for women at increased risk of having a fetus with DS. A policy of offering amniocentesis to all women at increased risk by virtue of maternal age or maternal serum screening was compared with one specifying amniocentesis only when high-risk women also had sonographic markers of fetal DS. The sonographic detection rate and screen-positive rate were varied from 40% to 90% and 5% to 30%, respectively, and the amniocentesis-related pregnancy loss rate was assumed to be one in 200. Using targeted ultrasonography to determine which high-risk women should have an amniocentesis, 56% of 7025 fetuses with DS would be missed. Among women at highest risk (both advanced maternal age and positive serum screening results), the detection rate for serum screening would be 89%, but adding sonography reduced this rate to 54%. Even when the sonographic detection rate has increased to 80% and the screen-positive rate was reduced to 10%, 42% of all DS cases would be missed. Many women with normal sonographic findings remain at high risk of having a fetus with DS. Using ultrasound adjunctively in high-risk women will result in many cases being missed. At present, at least, ultrasonography is insufficiently sensitive to rule out a fetus with DS in women at risk. Women who are not certain about whether to have amniocentesis because of possible complications should have an opportunity to inquire about the benefits and risks of ultrasound for the detection of DS as well as the risk of procedure-related fetal loss.

Effect on down syndrome screening performance of adjusting for marker levels in a previous pregnancy

In prenatal screening for Down syndrome, serum marker values can be adjusted using values from a previous pregnancy to avoid the problem of women having a high chance of recurrent false-positive results. We investigate the effect of such adjustment on overall screening performance. Monte Carlo simulation was used to investigate the effect of this adjustment on five widely used screening tests for Down syndrome (Triple, Quadruple, Combined, serum Integrated, Integrated tests). Adjustment for screening marker values (expressed in multiples of the median, (MoM)) in a previous pregnancy improved screening performance. The detection rate for a 1% false-positive rate (FPR) increased from 54 to 59% with the Triple test, from 63 to 68% with the Quadruple test, from 70 [corrected] to 75% for the Combined test, from 70 [corrected] to 76% for the serum Integrated test, and from 85 to 88% for the Integrated test. The FPR for an 85% detection rate decreased from 10 to 7.9%, 7.1 to 4.9%, 4.9 to 3.7%, 4.7 to 2.9% and 1.1 to 0.7% respectively for the five tests. Among women who have had a false-positive result in a previous pregnancy, adjustment substantially lowers the false-positive rate, for example, from 18 [corrected] to 7.3% with the Combined test using a 1 in 250 risk cut-off. MoM adjustment for values in a previous pregnancy improves overall screening performance and substantially reduces the high recurrent false-positive rate. This adjustment can be routinely applied in screening programmes through the screening software used to interpret a woman's screening results.

The effect of image size on screen‐positive rates for nuchal translucency screening

It has been shown previously that the absolute measurement of nuchal translucency (NT) thickness, one of the most effective screening tests for fetal Down syndrome, significantly decreases with increasing image size. We undertook a prospective study to assess whether this effect materially alters the NT-derived risk estimation for fetal Down syndrome. In 350 women, NT was measured at both 100 and 200% image sizes. The median NT measurement at 200% was 8% smaller than at 100%. The screen-positive rates at 100 and 200% image sizes were 5.1% (18/350) and 2.3% (8/350), respectively (P= 0.048). Altering the image magnification settings is likely to decrease the sensitivity of NT-derived Down syndrome risk estimation. Further study is required to test the effect of our finding on the sensitivity of NT screening and to assess whether adjustments in gain settings mitigate the effect.

OC38.04: The implementation of the integrated screening test for Down syndrome in a government hospital

OC38.04: The implementation of the integrated screening test for Down syndrome in a government hospital

Options for Down Syndrome Screening: What Will Women Choose?

Down syndrome screening has been offered to pregnant women since the early 1980s. Protocols have changed as research confirmed improvements that result in higher detection rates and lower false-positive rates. Results from 2 clinical trials evaluating screening protocols that include ultrasound measurement of nuchal translucency and biochemical testing in the first and second trimester are now available. First-trimester screening is an option if there are adequate ultrasound, diagnostic, and counseling services available. Regional variation in the availability of these services may limit the implementation of first-trimester screening. Combining screening tests for Down syndrome from both trimesters as an integrated test offers the highest detection rate with the lowest false-positive rate. The possibility of avoiding a positive screen will make this an attractive option for some. Timing, detection rate, false-positive rates, and personal factors influence the decision women make regarding screening versus diagnostic testing. This article reviews the efficacy of current protocols for Down syndrome screening. Accurate information about available screening tests will facilitate informed decisions about screening and testing.

Technical standards and guidelines: Prenatal screening for Down syndrome: This new section on “Prenatal Screening for Down Syndrome,” together with the new section on “Prenatal Screening for Open Neural Tube Defects,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories

Technical standards and guidelines: Prenatal screening for Down syndrome: This new section on “Prenatal Screening for Down Syndrome,” together with the new section on “Prenatal Screening for Open Neural Tube Defects,” replaces the previous Section H of the American College of Medical Genetics Standards and Guidelines for Clinical Genetics Laboratories *

First-trimester screening for trisomy-21 using a simplified method to assess the presence or absence of the fetal nasal bone

To determine the benefit of including nasal bone assessment in addition to standard first-trimester markers (nuchal translucency, free beta human chorionic gonadotropin and pregnancy-associated plasma protein A) as a screening test for Down syndrome, using a strict criterion for classification of nasal bone absence. Nasal bone assessment was conducted in 2411 patients with crown-rump length between 45 and 84 mm, including 15 patients with Down syndrome. A patient was considered to have an absent nasal bone only if there was no evidence of present nasal bone. Unlike other studies, nasal bone was classified as present when there was evidence of a thin echogenic line under the skin. Simulation studies were conducted to assess the detection rate and false-positive rate of a combined first-trimester screening protocol including nasal bone assessment. There were 9 of 2396 (0.4%) unaffected cases with absent nasal bone (95% confidence interval 0.2%, 0.7%) and 8 of 15 (53.3%) Down syndrome cases (95% confidence interval 26.6%, 78.7%). Using a 1 in 250 risk cut-off, the detection rate of standard first-trimester screening was 87%, with a false-positive rate of 4.3%. Incorporating nasal bone measurement improved the detection rate of Down syndrome to 90% and reduced the false-positive rate to 2.5%. The use of a strict criterion to determine nasal bone absence leads to fewer cases classified as absent and may simplify the implementation of nasal bone as a marker for first-trimester screening, resulting in lower false-positives and higher detection, compared with other current screening protocols.

A comparison of Australian and UK obstetricians' and midwives' preferences for screening tests for Down syndrome

To establish and compare obstetricians' and midwives' preferences for hypothetical prenatal screening tests for Down syndrome. A cross-sectional questionnaire survey was completed by 296 obstetricians and midwives at two teaching hospitals: one in Melbourne, Australia (n = 175), and one in London, UK (n = 94). Conjoint analysis was undertaken using random effects probit regression. No significant differences were seen in any measurements when comparing obstetricians in Australia and the UK or midwives in Australia and the UK. Obstetricians and midwives shared similar relative values regarding the importance of the detection rate of the screening tests. However, obstetricians placed higher relative values on both timing of prenatal tests and risk associated with the subsequent diagnostic test than did midwives when considering optimal tests to offer women. Marginal rates of substitution suggest that, compared with midwives, obstetricians would wait longer and accept a greater decrease in detection rate for a test if it was safer. Younger midwives placed higher value on both detection rate and safety of prenatal tests than older midwives. Female obstetricians placed higher value on the timing of a test than male obstetricians. Obstetricians in Australia and UK placed almost identical importance on test attributes, as did the midwives in the two countries. However, different attitudes towards tests were seen between obstetricians and midwives.

Historical Perspectives

This month’s Historical Perspectives is in a slightly different format, but should be of considerable interest to readers of NeoReviews. Professor Nicholas Wald is an epidemiologist who has evaluated and written about a variety of topics, but he is best known for his work on screening methods, particularly in the area of maternal serum alpha-fetoprotein (AFP) and fetal abnormalities. Because of his continuing heavy commitments and to minimize the disruption of his schedule, I posed a number of questions to him, to which he responded with detailed answers. Before moving to his responses, some background information seems in order. Shortly before publication of the article highlighted this month, evaluation of amniotic fluid in cases of open spina bifida and other neural tube defects had shown increased levels of AFP. (1) Somewhat later, it was shown that abdominal wall defects, as well as neural tube defects, could contribute to increased levels of amniotic fluid AFP. (2) In his responses, Professor Wald documents the sequence of events that followed, noting that Professor David Brock in Edinburgh described the association of increased levels of maternal serum alpha-fetoprotein (MSAFP) with fetal anencephaly, which triggered the idea that this also might be true of open spina bifida. Thus, MSAFP was used as a screening tool for the detection of neural tube and abdominal wall defects. Elevated MSAFP levels were noted in other “at-risk” pregnancies (3) and twin pregnancies. (4) To provide better standardization, Professor Wald introduced the concept of “multiples of the median” (MoM) at different gestational ages. Approximately a decade passed before the association was made between low MoMs for AFP and chromosomal defects, particularly Down syndrome. Soon thereafter, several other serum markers for Down syndrome were described, and by linking them to maternal age, screening became increasingly valuable. In the early 1980s, Dr …

First‐trimester combined ultrasound and biochemical screening for Down syndrome in routine clinical practice

To assess the effectiveness of combined ultrasound and biochemical (CUB) screening for chromosome abnormalities in singleton pregnancies in a routine antenatal clinic and laboratory setting. Women whose pregnancies fell within the gestational age range of 11 to 14 weeks by ultrasound assessment were offered CUB screening on the basis of measurement of nuchal translucency (NT), maternal serum free beta-human chorionic gonadotrophin (FbetahCG) and pregnancy-associated plasma protein A (PAPP-A). NT measurements were obtained using a standardised method defined by the Fetal Medicine Foundation and FbetahCG, and PAPP-A were measured using the DELFIA immunoassay system. Each screening marker measurement was converted to a multiple of the appropriate gestational median and a risk was derived using previously published parameters for each marker in chromosomally abnormal and unaffected pregnancies. A combined risk of Down syndrome and of trisomy 18/13, incorporating the maternal age risk, was calculated for all women. Invasive diagnostic testing was offered to women whose combined risk exceeded the cut-off risk of 1 in 250 (term). Five thousand and eighty-four women accepted a first-trimester screening test for Down syndrome, representing 75% of the eligible booking population. Out of the population eligible for CUB screening at the time of booking, NT measurements were obtained from 93% at the first clinic visit and 7% had to return for a second attempt. After excluding women who defaulted on a return visit, satisfactory NT measurements were obtained in 99.5% of pregnancies. Fifteen cases of Down syndrome and eleven pregnancies with other chromosome abnormalities were ascertained. The detection rate for Down syndrome was 93% (14/15) at a false-positive rate of 5.9% and for all chromosome abnormalities it was 96% (25/26) at an overall false-positive rate of 6.3%. CUB screening offers a significant improvement in sensitivity over second-trimester biochemical screening and is deliverable within a routine prenatal clinical setting.

Sialic acid-deficient invasive trophoblast antigen (sd-ITA): a new urinary variant for gestational Down syndrome screening.

Invasive trophoblast antigen (ITA), also known as hyperglycosylated hCG, is a glycosylation variant of hCG produced by invasive cytotrophoblast cells. Publications show that ITA is potentially a sensitive test for Down syndrome screening, reportedly detecting 38 and 80% of cases at a 5% false-positive rate in the first and second trimesters of pregnancy respectively. ITA has six oligosaccharides varying greatly in terminal sialic acid content (0-19 residues), leading to wide-charge heterogeneity. With the objective of developing an improved Down syndrome screening test, we examined the charge, or sialic acid variants, of ITA. Twenty urine samples were collected from the 16th to 18th week of gestation from 10 patients with trisomy 21 fetuses, demonstrated by karyotype analysis, and from 10 patients with normal karyotype pregnancies. Proteins in each sample were separated by preparative isoelectric focusing. Fractions were collected, pooled into the pl ranges of 3.0 to 4.0, 4.1 to 5.0, 5.1 to 6.0 and 6.1 to 7.0 and assayed for ITA. A difference in the distribution of ITA charge variants was demonstrated between cases and controls, most apparent in the less acidic (pl 5.1-7.0) range. The controls and Down syndrome samples contained 26.7 +/- 14% versus 45.6 +/- 20%, respectively, of the less acidic form of ITA (P = 0.02). The ITA in Down syndrome cases is composed of a much higher proportion of less acidic ITA. This could be the major source of elevated levels of ITA in Down syndrome pregnancies. It is postulated that the development of a new assay specifically measuring ITA that is deficient in sialic acid might enhance the utility of the already highly sensitive screening tests for Down syndrome.

Do women prefer to have screening tests for Down syndrome that have the lowest screen-positive rate or the highest detection rate?

To assess whether women have a preference for Down syndrome screening test performance. A structured questionnaire exploring women's preferences for screening test performance was administered to women attending their first prenatal visit who wished to have Down syndrome screening performed. One hundred and twenty women were interviewed. The majority of women (n=80) chose a screening test with a low screen-positive rate rather than the highest detection rate. The reasons given for this preference were a desire to minimise the risk of miscarriage of a normal baby and a belief that a detection rate of 80 to 90% was acceptable. However, older women (>37 years) chose a test with the highest detection rate possible, regardless of the higher screen-positive rate, preferring to miscarry a normal baby as a result of a diagnostic test rather than miss the detection of a baby with Down syndrome. Preferences were not influenced by previous screening experience. Women express different preferences for screening test performance. Maternal age rather than previous screening experiences appears to be the major influence in these choices.

Women's preferences for reporting of Down syndrome screening results.

The aim of this study was to determine whether women prefer the results of screening for Down syndrome tests to be reported as the risk of Down syndrome in early pregnancy at the time of the screening test or the risk at delivery (which takes into account the number of Down syndrome pregnancies that will be spontaneously lost before birth). A structured questionnaire. A tertiary hospital antenatal clinic. One hundred and fifteen English-speaking women who expressed an interest in having screening tests for Down syndrome performed. A structured questionnaire exploring women's preferences for risk reporting was self administered by women attending for their first antenatal visit. Women's preference for reporting of screening test results as risk at time of test, risk at birth or both, and the reasons for this preference. The majority (n = 82) of women preferred to have both the risk of Down syndrome at the time of screening and at the time of birth reported. The most common reason (n = 60) given for this preference was a desire to have as much information available as possible so that an informed decision regarding further investigations could be made. The majority of women prefer to receive Down syndrome screening results as both the risk at the time of the test and the risk at birth.

Womens' preference in Down syndrome screening.

To determine the knowledge of pregnant women about prenatal tests, and what tests they would choose if offered. Also, the preference of pregnant women for second-trimester or first-trimester screening was assessed. Pregnant women receiving antenatal care in a decentralized primary care system (n=80), and pregnant women that were offered a prenatal diagnosis at the Academic Medical Centre (n=195), were asked to complete a questionnaire. The response rate was over 80%. Most women in both groups preferred a screening test for Down syndrome to be performed in the first trimester of pregnancy. A combination of nuchal translucency measurement and first-trimester serum screening was the option of choice. The screening possibilities for Down syndrome were less well known to the women in the low-risk group compared with the women in the high-risk group. The offer of a prenatal screening test would have been declined by more than 30% of women at low risk for carrying a fetus with Down syndrome. Our results show that women prefer screening for Down syndrome to be performed in the first trimester of pregnancy, using both serum and ultrasound tests. In women at low risk for Down syndrome the knowledge of prenatal screening methods was less, as well as the acceptance of prenatal screening being lower.

Biochemical screening for Down syndrome in pregnancies following renal transplantation.

To assess the performance of the double marker test [free beta-human chorionic gonadotrophin (beta-hCG) and alpha-fetoprotein (AFP)] as a screening test for Down syndrome in pregnant patients who had a prior renal transplant. A retrospective study. The Fetal Medicine Unit, Royal Free Hospital, London, UK. Detailed records of 14 post-renal transplant pregnancies were obtained from the Renal Unit of our hospital where the patients were followed up. The serum concentrations of urea, creatinine, free beta-hCG and AFP at the time of the double marker test were recorded, with a cut-off point of 1:250 for the double marker test. A control group of 14 normal pregnancies matched for age, parity and gestational age was used. The Mann-Whitney U-test and t-tests of unequal variance were applied to compare parameters of the study and the control groups. Two patients in each group were high risk for Down syndrome and amniocentesis revealed normal karyotype. No babies with Down syndrome were delivered in either group. Regression analysis showed significant correlation between free beta-hCG and urea concentrations (p<0.001) and free beta-hCG and creatinine concentrations (p<0.001), but not for AFP. The present study demonstrates that residual renal function alterations persisting after renal transplantation can affect the levels of free beta-hCG and AFP, thus resulting in false-positive screening for Down syndrome. First trimester nuchal translucency (NT) measurement in combination with second trimester ultrasonographic markers can be used in these patients, or alternatively the free beta-hCG levels should be corrected according to the serum creatinine levels.

Second-trimester ultrasound to detect fetuses with Down syndrome: a meta-analysis.

Second-trimester prenatal ultrasound is widely used in an attempt to detect Down syndrome in fetuses, but the accuracy of this method is unknown. To determine the accuracy of second-trimester ultrasound in detecting Down syndrome in fetuses. English-language articles published between 1980 and February 1999 identified through MEDLINE and manual searches. Studies were included if they recorded second-trimester findings of ultrasonographic markers, chromosomal abnormalities, and clinical outcomes for a well-described sample of women. A total of 56 articles describing 1930 fetuses with Down syndrome and 130 365 unaffected fetuses were included. Articles were independently reviewed, selected, and abstracted by 2 reviewers. Discrepancies in data abstraction were resolved by consensus with a third reviewer. Overall estimates of sensitivity, specificity, and positive and negative likelihood ratios were calculated for the following markers: choroid plexus cyst, thickened nuchal fold, echogenic intracardiac focus, echogenic bowel, renal pyelectasis, and humeral and femoral shortening. Results were stratified by whether markers were identified in isolation or in conjunction with fetal structural malformations. When ultrasonographic markers were observed without associated fetal structural malformations, sensitivity for each was low (range, 1%-16%), and most fetuses with such markers had normal outcomes. A thickened nuchal fold was the most accurate marker for discriminating between unaffected and affected fetuses and was associated with an approximately 17-fold increased risk of Down syndrome. If a thickened nuchal fold is used to screen for Down syndrome, 15 893 average-risk women or 6818 high-risk women would need to be screened for each case of Down syndrome identified. For each of the other 6 markers, when observed without associated structural malformations, the marker had marginal impact on the risk of Down syndrome. Because the markers were detected in only a small number of affected fetuses, the likelihood of Down syndrome did not decrease substantially after normal examination findings (none of the negative likelihood ratios were significant). A thickened nuchal fold in the second trimester may be useful in distinguishing unaffected fetuses from those with Down syndrome, but the overall sensitivity of this finding is too low for it to be a practical screening test for Down syndrome. When observed without associated structural malformations, the remaining ultrasonographic markers could not discriminate well between unaffected fetuses and those with Down syndrome. Using these markers as a basis for deciding to offer amniocentesis will result in more fetal losses than cases of Down syndrome detected, and will lead to a decrease in the prenatal detection of fetuses with Down syndrome.