Use of genetic sonography for adjusting the risk for fetal Down syndrome

Systematic evaluation of ultrasound findings known to be associated with trisomy 21, at an appropriate gestational age, has been referred to as a genetic sonogram. A number of high-risk centers performing genetic sonography have reported detection of ultrasound abnormalities in the majority of fetuses with fetal Down syndrome. However, nonspecific markers are more commonly observed than structural abnormalities, which are detected in less than 20% of cases in a nonselected population. Also, the actual sensitivity of a genetic sonogram will depend on various factors including the markers sought, gestational age, reasons for referral, and of course the quality of the ultrasound. Appropriate use of a genetic sonogram can help to modify the risk of fetal Down syndrome by decreasing the risk when the ultrasound is normal, or increasing the risk when specific ultrasound markers are detected. The postultrasound risk can be estimated by applying specific likelihood ratios, reflecting the strength of individual markers, with the a priori risk based on maternal age alone, or combined with biochemical markers when known. We review this approach of age-adjusted ultrasound risk assessment for fetal Down syndrome and illustrate how the risk can be estimated. Individual sonographic markers are also discussed.     

New contingent sequential screening model for Down syndrome based on the combined test associated with modified genetic sonography

Abstract

Objective: The aim of this study is to evaluate the possibility of implementing a contingent sequential screening test for Down syndrome (DS) based on the combined test (CT) associated with modified genetic sonography (MGS). We evaluate sensitivity (Sen), false positive rate (FPR), and economic costs.

Method: We compiled data from the results of a prospective screening programme for DS during a 5-year study period (July 2005–December 2011). Pregnancies were offered the CT as the first step in the contingent sequential test. We identified an intermediate risk group (1/101–1/1000) using CT results, and offered these individuals a MGS (major malformation and nuchal fold).

Results: A total of 19?440 pregnancies (103 chromosome abnormalities and 66 cases of DS) were administered the CT. We performed a MGS on 99.6% of individuals in the intermediate risk group (2188/2197); in this group, we observed 22 chromosome abnormalities (17 DS). The CT provided a Sen for DS of 80.30% (95%CI: 68.68–89.07) (53/66), and a Sen for all chromosome abnormalities of 76.70% (95%CI: 67.34–84.46) (79/103), with a FPR of 3.79% (95%CI: 3.52–4.05) (732/19?374). The contingent sequential strategy produced a Sen for DS of 81.82% (95%CI: 70.39–90.24) (54/66) and a Sen for all chromosome abnormalities of 79.61% (95%CI: 70.54–86.91) (82/103), with a FPR of 1.16% (95%CI: 1.02–1.33) (224/19?457). The economic costs of the CT and the contingent sequential model were 9?70?275 Euros and 9?41?716 Euros, respectively.

Conclusions: We present a new sequential contingent strategy for DS screening and demonstrate its usefulness for reducing FPR while maintaining a high level of Sen for DS, without requiring an increase in economic costs.     

The use of genetic sonography to reduce the need for amniocentesis in women at high-risk for Down syndrome

Much information has been published regarding the use of second-trimester genetic sonography for the prenatal detection of Down syndrome by examining multiple aneuploidy markers. Among high-risk mothers (advanced maternal age, abnormal triple screen, or both), while many undoubtedly will choose to have invasive testing as a first option, others will instead use the information derived from genetic sonography to obtain an adjusted risk for Down syndrome to guide their decision about genetic amniocentesis. Accordingly, it is imperative that these patients have accurate and detailed counseling regarding their degree of risk reduction when the genetic sonogram is normal. This article reviews the use of second trimester genetic sonography in reducing the need for amniocentesis in the high-risk patient. At our institution, in high-risk patients when the genetic ultrasound is normal, the amniocentesis rate has been only 3%. We have found that genetic sonography is a patient-driven service, and that the information obtained at the time of ultrasound is an important component of the patient's decision of whether or not to proceed with invasive testing.     

Early genetic sonogram for Down syndrome detection

OBJECTIVE: The purpose of this study was to determine the Down syndrome sensitivity of early genetic sonography (14-<16 weeks of gestation) and to compare its diagnostic accuracy with that later in the mid trimester (16-24 weeks of gestation). STUDY DESIGN: Nuchal thickness, humerus and femur lengths, hyperechoic bowel, hypoplastic fifth digit (clinodactyly), and any gross anatomic defects were measured or ascertained in singleton pregnancies that were undergoing genetic amniocentesis. Multiple stepwise logistic regression analysis was used to determine the significant sonographic markers for Down syndrome detection in each group. Multivariate gaussian algorithms that included maternal age were used to estimate patient-specific Down syndrome risk. Sensitivity and false- positive rates, receiver-operating characteristic curves, and area under the curves were calculated and compared for both groups. RESULTS: There were 1,727 pregnancies with 22 Down syndrome fetuses (1.27%) in the early group versus 3,914 pregnancies with 86 Down syndrome fetuses (2.2%) in the later group. The mean +/- SD ages were 15.5 +/- 0.4 weeks versus 17.6 +/- 1.4 weeks, respectively. Early genetic sonography (14-<16 weeks) had a 100% detection rate, with a 21.2% false-positive rate. The early versus later genetic sonography had an 81.8% versus 61.6% detection rate, respectively, at a fixed 4.8% false-positive rate. Early sonography had significantly higher diagnostic accuracy (area under the curve, 0.962 vs 0.871, respectively; P =.005). In fetuses at 14 to 15 weeks, the genetic sonography was also highly accurate, with 100% detection with a 21.9% false-positive rate. CONCLUSION: Early genetic sonography is highly sensitive and statistically superior to later ultrasonography for Down syndrome detection. Early midtrimester sonography achieved a diagnostic accuracy similar to that currently reported for first-trimester nuchal translucency.     

The current role of sonography in the detection of Down syndrome

The biparietal diameter (BPD)/femur length ratio, nuchal skin thickening, and measured-to-expected femur length ratio have been suggested as sonographic predictors of Down syndrome. In an effort to validate these parameters, we compared their individual and combined prevalence in 22 fetuses with Down syndrome. Using our normative data, the sensitivity and specificity of the BPD/femur length ratio were 36.4 and 93.4%, respectively. Assuming an incidence of Down syndrome in the general population of one in 1000, the estimated positive predictive value was 0.6%. When the BPD/femur length ratio, nuchal skin thickening, and measured-to-expected femur length ratio were combined, the sensitivity was improved (36.4 versus 45.5%) without significantly altering the specificity (93.4% versus 92.3%). A large prospective study is required to verify the utility of sonographic predictors of Down syndrome before their application can be recommended.     

叶酸代谢相关基因的多态性与唐氏综合征的关系

目的 研究叶酸代谢中亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)基因的的遗传多态性是否与唐氏综合征(down syndrome,DS)的发生相关. 方法选择100例生育过DS患儿的汉族母亲为研究组和100例相匹配的汉族母亲为对照组,使用PCR-RFLP和MGB-Taqman实时PCR方法检测MTHFR 677和MTHFR 1298的基因型,化学发光法检测血浆同型半胱氨酸(homocysteine,HCY)的水平. 结果 MTHFR 677和MTHFR 1298一个和/或两个等位基因的变异可使生育DS患儿的风险率分别增加2.37倍(95%CI:1.32～4.27)和1.97倍(95%CI:1.04～3.75).同时合并MTHFR 677CT和1298AC/CC可使DS的发病风险率显著增高,OR=5.62(95%CI:1.86～17.03),而MTHFR 677TT合并1298AC/CC的基因型组合使OR=11.84(95%CI:1.39～100.62).研究组血浆HCY水平显著高于对照组[(9.04±3.85)μmol/L和(6.53±2.06)μmol/L,P<0.01].MTHFR 677一个和/或两个等位基因C→T的变异,使研究组和对照组HCY水平均显著增加(P<0.05).单纯存在MTHFR 1298A/C时两组血浆HCY水平无统计学差异(P>0.05).同时存在MTHFR 677CT/TT和1298AC/CC基因组合可使血浆HCY水平增高(P<0.05).结论 HCY/叶酸代谢相关基因的多态与汉族妇女生育DS患儿的风险相关,且可能存在基因的协同作用.     

First- and second-trimester evaluation of risk for Down syndrome

OBJECTIVE: To investigate the differences in costs and outcomes of Down syndrome screening using data from the First and Second Trimester Evaluation of Risk (FASTER) Trial. METHODS: Seven possible screening options for Down syndrome were compared: 1) Triple Screen-maternal serum alpha fetoprotein, estriol, and hCG; 2) Quad-maternal serum alpha fetoprotein, estriol, hCG, and Inhibin A; 3) Combined First-nuchal translucency, pregnancy-associated plasma protein A (PAPP-A), free beta-hCG; 4) Integrated-nuchal translucency, PAPP-A, plus Quad; 5) Serum Integrated-PAPP-A, plus Quad; 6) Stepwise Sequential-Combined First plus Quad with results given after each test; and 7) Contingent Sequential-Combined First and only those with risk between 1:30 and 1:1,500 have Quad screen. The detection rates for each option were used given a 5% false-positive rate except for Contingent Sequential with a 4.3% false-positive rate. Outcomes included societal costs of each screening regimen (screening tests, amniocentesis, management of complications, and cost of care of Down syndrome live births), Down syndrome fetuses identified and born, the associated quality-adjusted life years, and the incremental cost-utility ratio. RESULTS: Based on the screening results derived from the 38,033 women evaluated in the FASTER trial, the Contingent Sequential screen dominated (lower costs with better outcomes) all other screens. For example, the Contingent Sequential cost 32.3 million dollars whereas the other screens ranged from 32.8 to 37.5 million dollars. The Sequential strategy led to the identification of the most Down syndrome fetuses of all of the screens, but at a higher cost per Down syndrome case diagnosed ($719,675 compared with $690,427) as compared with the Contingent Sequential. Because of the lower overall false-positive rate leading to fewer procedure-related miscarriages, the Contingent Sequential resulted in the highest quality-adjusted life years as well. The Contingent Sequential remained the most cost-effective option throughout sensitivity analysis of inputs, including amniocentesis rate after positive screen, rate of therapeutic abortion after Down syndrome diagnosis, and rate of procedure-related miscarriages. CONCLUSION: Analysis of this actual data from the FASTER Trial demonstrates that the Contingent Sequential test is the most cost-effective. This information can help shape future policy regarding Down syndrome screening.     

Second-trimester genetic sonography in patients with advanced maternal age and normal triple screen

OBJECTIVE: To estimate the value of second-trimester genetic sonography in detecting fetal Down syndrome in patients with advanced maternal age (at least 35 years) and normal triple screen. METHODS: Since July 1999, a prospective collection and recording of all individual triple screen risks for fetal Down syndrome was initiated for all patients with advanced maternal age presenting in our ultrasound unit for second-trimester genetic sonography. Genetic sonography evaluated the presence or absence of multiple aneuploidy markers. Outcome information included the results of genetic amniocentesis, if performed, and the results of pediatric assessment and follow-up after birth. RESULTS: By June 2001, 959 patients with advanced maternal age and normal triple screen were identified. Outcome information was obtained in 768 patients. The median risk for fetal Down syndrome based on maternal age was 1:213 (range 1:37-1:274). The median risk for fetal Down syndrome based on triple screen results was 1:1069 (range 1:275-1:40,000). A total of 673 patients had normal genetic sonography, and none (0%) had Down syndrome; 95 had one or more aneuploidy markers present, and four (4.2%) had fetuses with Down syndrome. The triple screen risks for these four fetuses ranged from 1:319 to 1:833. CONCLUSION: This study suggests that patients with advanced maternal age and normal genetic sonography carried very little risk for Down syndrome. The use of genetic sonography may increase the detection rate of fetal Down syndrome in this group of pregnant women.     

Maternal serum alpha-fetoprotein, age, and Down syndrome risk

Before the discovery that an association existed between low maternal serum alpha-fetoprotein levels and Down syndrome, the ability to detect Down syndrome pregnancies was limited to women aged greater than or equal to 35, whose individual risks were sufficiently high (greater than or equal to 1:270 in the second trimester) to justify offering amniocentesis. If such women were to opt for that procedure, about 20% of all cases of Down syndrome could be detected. It is now possible to identify an additional 20% of all Down syndrome pregnancies in women under age 35, with the use of a screening process that combines a woman's maternal serum alpha-fetoprotein level and her age. We present a method whereby a woman's individual odds for Down syndrome can be calculated by combining the maternal serum alpha-fetoprotein measurement with her age, on the basis of published age-related Down syndrome risk data and on maternal serum alpha-fetoprotein distributions for unaffected and Down syndrome pregnancies. These individual odds calculations provide the basis both for establishing maternal serum alpha-fetoprotein/Down syndrome screening cutoffs and for counseling.     

Optimal risk cut-offs for Down syndrome contingent maternal serum screening

Objectives: The objective of this study is to identify the optimal cut-off points of contingent serum screening excluding nuchal translucency (NT) measurement, to categorize the risk level in the first trimester.

Methods: A prospective database of women undergoing contingent serum screening, without NT measurement, was reviewed. In conventional categorization, the results of first-trimester screening were categorized into high risk (>1:30) (invasive diagnosis was offered); intermediate risk (1:30–1:1500) (second-trimester screening was needed); and low risk (<1:1500) (no further test). We recategorized the risk levels using various upper and lower cut-offs and compared detection rates, false-positive rates, and rates of intermediate risk.

Results: Among 24,874 women, the prevalence of Down syndrome was 1:691. The previously agreed cut-offs had a detection rate of 88.9% and a false-positive rate of 8.5% with high rate of intermediate risk (38.2%). Re-categorization provided the optimal lower and upper cut-offs 1/900 and 1/50, respectively, giving a detection rate of 86.1%, a false-positive rate of 8.1%, and a rate of intermediate risk of 24.8%.

Conclusions: This is the first study on contingent serum screening without NT measurement which shows a high detection rate with an acceptable false-positive rate. The optimal cut-offs to categorize the risk levels of the upper and the lower cut-off was 1:30–1:50 and 1:900, respectively.     

Maternal serum S100 protein in normal and Down syndrome pregnancies.

Protein S100 is a low molecular weight (10-12 kD) calcium-binding protein the beta subunit of which is coded for at the 22.2-22.3 region of the long arm of chromosome 21. This region has also been shown to be responsible for the phenotypic expression of Down syndrome. Previous studies demonstrated increased immunoreactivity to protein S100 in brain tissue from adults with Down syndrome. We have previously observed a higher concentration of S100 protein in the fetal blood of trisomy 21 fetuses compared with normal subjects. The aim of this study was therefore to investigate the use of measuring S100 protein concentration in maternal blood for Down syndrome screening. Maternal blood was taken at the time of chorionic villus sampling or cordocentesis (11-38 weeks' gestation) for fetal karyotyping. Protein S100 was measured by a two-site immunoradiometric assay (S-100 IRMA, Sangtec). There was no significant difference in the concentration of maternal S100 protein between normal and trisomy 21 pregnancies (p<0.10). Moreover, there was no significant association between maternal serum S100 protein concentration and gestational age (r(s)=0.27, p=0.07), maternal age (r(s)=-0.17, p=0.7) or maternal weight (r(s)=-0.013, p=0.9). This study shows that measurement of maternal serum S100 protein concentration does not appear to have a value in Down syndrome screening.     

Inaccurate estimation of risk in second trimester serum screening for Down syndrome among women who have already had first trimester screening

Problems can arise in prenatal screening for Down syndrome when tests are performed in the first and second trimester and some women who have a negative first trimester test have a second trimester serum test. The second test result does not usually take account of the previous one being negative. Even if it does, it is often inaccurate. Using published data the extent of the error was examined. The age-specific risk of an affected pregnancy in such women will be lower than if no first trimester test had been performed. The distributions of the screening markers in affected and unaffected pregnancies will be different from those in unscreened women. If the appropriate age-specific risk and marker distributions are not used, error will arise. For example, a 35-year-old woman with nuchal translucency (NT), pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotrophin (hCG) levels at the normal median would have a risk of 1 in 6500. If she then had the Triple Test with alpha-fetoprotein (AFP), unconjugated oestriol, and hCG levels of 0.7, 0.7 and 1.5 multiples of the median (MoM), respectively, her risk, ignoring the previous result, would be overestimated (1 in 95 compared with the correct estimate of 1 in 705). If the previous result was included, but the age-specific risk and second trimester marker distributions were not revised, her risk would be underestimated (1 in 820). If the correct age-specific risk and screening marker distributions were used, risk estimates would be accurate, but two tests would be less efficient than integrating all the screening information into a single test. The practice of offering second trimester serum screening to women who have already been screened is best avoided.     

Periconceptional exposure to contraceptive pills and risk for Down syndrome.

OBJECTIVE: There are some studies which analyzed the relationship between prenatal exposure to oral contraceptives (OCs) and Down syndrome, with conflicting results even in women using OCs and conceiving at different intervals after discontinuing the use of contraceptive pills. We analyzed the risk for Down syndrome in infants of women who become pregnant while taking OC. STUDY DESIGN: We used the data from the Spanish Collaborative Study of Congenital Malformations (ECEMC). The ECEMC is a case-control study and surveillance system. For each malformed infant (case), the next non-malformed infant of the same sex born in the same hospital is selected as a control subject, from whom the collaborating physicians collected the same data as for the malformed infant. For the present study, we used two different approaches. First, the pair-matching analysis. Second, a case-control using the rest of the total of 17,183 controls from the ECEMC database with specified data on maternal use of OCs and maternal age. To control for maternal age, we used a logistic regression analysis. RESULTS: The results show an increased risk of 2.8-fold for infants with Down syndrome in women younger than 35 years of age if the mother became pregnant while she was taking OCs. We did not observe this result for women older than 34 years of age. CONCLUSION: Our results showed that the risk for Down syndrome in infants born to mothers with less than 35 years of age (as a group) who became pregnant while taking OCs is near the risk for Down syndrome of mothers with more than 34 years of age, women who are candidates for prenatal diagnosis. Thus, based on our results, one may consider the possibility of offering prenatal diagnosis for Down syndrome to young women who became pregnant while taking OCs.     

Biochemical screening for Down syndrome: patients' perception of risk.

OBJECTIVES: To determine the utility of the triple test in routine clinical practice and in addition to the document, the acceptability of a cut-off of 1:250 for invasive testing. DESIGN: Retrospective analysis of data from screening and invasive testing for Down syndrome over a 5-year period in Hull Maternity Hospital. Computer-based records were accessed and individual data drawn from case notes were analyzed. RESULTS: 14827 (78%) of all patients opted for the triple test. A positive result (1:250 or greater) was found in 586 (4%). Fifteen percent of this group refused further testing with amniocentesis. 0.08% requested amniocentesis despite a negative triple test result. Of the screened pregnancies the triple test and selective invasive testing identified nine out of 15 (60%) of Down syndrome cases. CONCLUSION: Sixty percent of Down syndrome pregnancies were identified with a 4% invasive testing rate. Fifteen percent of women who had a positive test did not agree with the cut-off of 1:250 and therefore declined invasive testing. Invasive procedure complication rates do not equate with patients' perception of Down syndrome.