Second-trimester Genetic Sonography Research Articles

Genetic sonography: the historical and clinical role of fetal echocardiography

The association of congenital heart defects with trisomy 21 was reported over 50 years ago and heart defects remain one of the most common and lethal abnormalities present postnatally in individuals affected by Down syndrome1–4. The purpose of this Editorial is to review the use of second-trimester fetal echocardiography as an adjunct to the genetic sonogram from a clinical perspective, based on my experience over the past 20 years5–13. The following topics are discussed as they relate to trisomy 21: (1) the incorporation of ultrasound evaluation of the fetal heart as part of the genetic sonogram and comparison of it with other screening modalities from a historical perspective; (2) the postnatal incidence of congenital heart defects; (3) the prenatal incidence of structural and functional heart abnormalities; (4) the relative risk for various cardiac findings; and (5) the suggested use of fetal echocardiography as part of the genetic sonogram given current screening technologies.

Second-Trimester Genetic Sonography After First-Trimester Combined Screening for Trisomy 21

Second-Trimester Genetic Sonography After First-Trimester Combined Screening for Trisomy 21

Role of Second-Trimester Genetic Sonography After Down Syndrome Screening

Role of Second-Trimester Genetic Sonography After Down Syndrome Screening

Role of Second-Trimester Genetic Sonography After Down Syndrome Screening

To estimate the effectiveness of second-trimester genetic sonography in modifying Down syndrome screening test results. The First and Second Trimester Evaluation of Risk (FASTER) aneuploidy screening trial participants were studied from 13 centers where a 15- to 23-week genetic sonogram was performed in the same center. Midtrimester Down syndrome risks were estimated for five screening test policies: first-trimester combined, second-trimester quadruple, and testing sequentially by integrated, stepwise, or contingent protocols. The maternal age-specific risk and the screening test risk were modified using likelihood ratios derived from the ultrasound findings. Separate likelihood ratios were obtained for the presence or absence of at least one major fetal structural malformation and for each "soft" sonographic marker statistically significant at the P<.005 level. Detection and false-positive rate were calculated for the genetic sonogram alone and for each test before and after risk modification. A total of 7,842 pregnancies were studied, including 59 with Down syndrome. Major malformations and 8 of the 18 soft markers evaluated were highly significant. The detection rate for a 5% false-positive rate for the genetic sonogram alone was 69%; the detection rate increased from 81% to 90% with the combined test, from 81% to 90% with the quadruple test, from 93% to 98% with the integrated test, from 97% to 98% with the stepwise test, and from 95% to 97% with the contingent test. The stepwise and contingent use of the genetic sonogram after first-trimester screening both yielded a 90% detection rate. Genetic sonography can increase detection rates substantially for combined and quadruple tests and more modestly for sequential protocols. Substituting sonography for quadruple markers in sequential screening was not useful. II.

Second-Trimester Genetic Sonography After First-Trimester Combined Screening for Trisomy 21

The purpose of this study was to evaluate the trisomy 21 screening performance of the first-trimester combined test followed by second-trimester genetic sonography. This retrospective cohort study included all women with singleton pregnancies undergoing combined screening followed by genetic sonography at 17 to 21 weeks from January 1, 2005, to January 31, 2008. Combined test trisomy 21 risks were multiplied by positive or negative likelihood ratios based on the second-trimester sonographic findings to determine the final trisomy 21 risk. Sonography was evaluated as the second part of (1) a stepwise sequential test applied to combined screen-negative pregnancies and (2) an integrated test applied to all combined screen patients regardless of the latter results. A final trisomy 21 risk of 1:270 or higher was considered screen-positive. A total of 2231 pregnancies underwent combined screening, which detected 7 of 8 Down syndrome cases (87.5%) at a 9.6% screen-positive rate. A total of 884 of these patients (39.6%), including 2 having fetuses with Down syndrome, had genetic sonography. Combined screening detected 1 of these trisomy 21 fetuses (50%) at a 15.7% screen-positive rate. Integrated ultrasound-based aneuploidy screening detected both trisomy 21 cases (100%) at a 22.7% screen-positive rate, whereas stepwise sequential ultrasound-based aneuploidy screening also detected both trisomy 21 fetuses (100%) but at a 28.3% screen-positive rate (P< .0001). Second-trimester genetic sonography after first-trimester combined screening may improve trisomy 21 detection at the expense of increasing screen-positive rates.

Role of Second-Trimester Genetic Sonography After Down Syndrome Screening

Role of Second-Trimester Genetic Sonography After Down Syndrome Screening

Genetic Sonography After First-trimester Down Syndrome Screening

Although second-trimester Down syndrome screening using maternal analytes was long accepted as the standard of care, first-trimester screening using both maternal analytes and fetal nuchal translucency measurement has become a viable alternative and may even be preferable, since it identifies approximately 90% of Down syndrome cases. This simulation study used published statistical parameters to determine whether following a first-trimester screening test with second-trimester sonography is an effective sequential screening protocol. Both stepwise screening (all patients have both a first-trimester screening and a second-trimester ultrasound exam) and contingent screening (all patients have a first-trimester screening; only those with a Down syndrome risk between 1/300 and 1/2500 have a second-trimester ultrasound exam) were evaluated. Serum analytes assessed in the first trimester included free β-human chorionic gonadotropin and pregnancy-associated plasma protein A. Ultrasound markers included nuchal translucency thickness and nasal bone in the first trimester, and nuchal fold, hyperechoic bowel, short humerus, short femur, echogenic intracardiac focus, pyelectasis, or a major abnormality in the second trimester. Combined first-trimester screening with maternal serum analytes and nuchal thickness detected 88.5% of Down syndrome cases at a false-positive rate of 4.2%. If women who were screen negative underwent a second-trimester genetic ultrasound and everyone whose fetus had at least one ultrasound marker was considered screen positive, another 8% of Down syndrome cases were identified at an additional false-positive rate of 13.2%. This protocol thus identified 96.5% of all Down syndrome cases at a total screen positive rate of 17.5%. In an alternative approach, the second-trimester ultrasound markers were converted into likelihood ratios that were used to modify the Down syndrome risk determined by the first-trimester screening test. This protocol identified a total of 94.1% cases at a total screen positive rate of 5.4%. In the contingent protocol, only women whose first-trimester risk of Down syndrome was between 1/300 and 1/2500 underwent second-trimester ultrasound, and sonographic markers were converted into likelihood ratios that were used to modify the Down syndrome risk determined by the first-trimester screening test. This yielded an overall Down syndrome detection rate of 93.3% and a total false-positive rate of 4.9%. Regardless of whether a stepwise sequential or contingent protocol is used, second-trimester genetic sonography may be considered as an alternative to second-trimester serum screening for maximizing the detection of Down syndrome at reasonable rates of false-positive findings.

Genetic sonography after first‐trimester Down syndrome screening

Approximately 90% of Down syndrome cases are detected during first-trimester screening. We aimed to determine the potential effectiveness of second-trimester genetic sonography as a sequential screen for Down syndrome. In this simulation study, published statistical parameters for first-trimester free beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A and nuchal translucency thickness, and second-trimester ultrasound markers (nuchal fold, hyperechoic bowel, short humerus, short femur, echogenic intracardiac focus, pyelectasis and major abnormality) were used to model the effectiveness of second-trimester genetic sonography combined with first-trimester screening. First-trimester combined screening alone resulted in a detection rate of 88.5% with a 4.2% false-positive rate. A follow-up genetic ultrasound examination in which only one sonographic marker was found and previous results were not taken into account would detect an additional 8% of Down syndrome cases for an additional false-positive rate of 13.2%. Using individual marker likelihood ratios to modify the first-trimester risk for screen-negative patients, genetic sonography detected an additional 6.1% of Down syndrome cases for an additional 1.2% false-positive rate, giving a total detection rate of 94.6% and a total false-positive rate of 5.4%. In a contingent protocol, in which genetic sonography would be performed only for patients with a first-trimester risk of between 1/300 and 1/2500, the detection rate was 4.8% and the false-positive rate was 0.7%, giving a total detection rate of 93.3% and a total false-positive rate of 4.9%. Second-trimester genetic sonography, if used properly, can be an effective sequential screen following first-trimester Down syndrome screening. Further studies on the role of the genetic sonogram as a follow-up to first-trimester combined screening are warranted.

Second-Trimester Prenatal Diagnosis of Total Arhinia

Arhinia is defined as the congenital absence of the nose. It is an extremely rare condition, which is usually associated with other craniofacial abnormalities. An extensive literature search revealed that the prenatal diagnosis of this anomaly has only been reported on 1 previous occasion at 29 weeks' gestation, and the diagnosis at birth has been reported only 29 times in the pediatric literature. 1-29 To our knowledge, there has not been a previously reported case of congenital arhinia diagnosed during the second trimester. This report describes the 2- and 3-dimensional sonographic appearance of arhinia shown during second-trimester genetic sonography and reviews this exceedingly rare craniofacial defect. Early diagnosis of this defect allows the patient to consider all her options regarding pregnancy management. The detection of arhinia in the second trimester provides evidence that this rare disorder can be diagnosed through appropriate evaluation of craniofacial anatomy on a comprehensive second-trimester sonographic examination.

First and second trimester evaluation of risk (FASTER) trial: The role of second trimester genetic sonography

OF SECOND TRIMESTER GENETIC SONOGRAPHY FERGAL MALONE, DAVID A. NYBERG, JOHN VIDAVER, ROBERT BALL, CHRISTINE H. COMSTOCK, GEORGE SAADE, RICHARD BERKOWITZ, SUSAN GROSS, LORRAINE DUGOFF, SABRINA CRAIGO, ILAN E. TIMOR, STEPHEN R. CARR, HONOR M. WOLFE, JACOB CANICK, MARY E. D’ALTON, Columbia University, New York, New York, Swedish Medical Center, Seattle, Washington, DM-STAT, Boston, Massachusetts, University of Utah, Salt Lake City, Utah, William Beaumont Hospital, Royal Oak, Michigan, UTMB, Galveston, Texas, Mount Sinai School of Medicine, New York, New York, Montefiore Medical Center, Bronx, New York, University of Colorado, Denver, Colorado, Tufts University, Boston, Massachusetts, NYU, New York, New York, Brown University, Providence, Rhode Island, UNC, Chapel Hill, North Carolina OBJECTIVE: To evaluate the role of 2nd trimester genetic sonography in a population that has already undergone 1st trimester Combined screening and 2nd trimester Quad screening. STUDY DESIGN: Unselected singleton pregnancies at 15 centers had 1st trimester Combined screening at 10-13 wks (nuchal translucency, PAPP-A, fbhCG), and 2nd trimester Quad screening at 15-18 wks (AFP, hCG, uE3, inhibin-A). Patients remaining at their local FASTER site for antenatal care also had a detailed genetic sonogram at 15 to 23 wks, to evaluate for major structural fetal anomalies and minor markers for aneuploidy. RESULTS: 8,533 patients had detailed 2nd trimester genetic sonography, including 62 cases of Trisomy-21. 1st trimester combined screen detected 84% (52/62) of T-21 (6.6% FPR); 2nd trimester Quad screen detected 88% (53/60) (11% FPR). In the 3 T-21 cases undetected by these screens, multiple markers were detected in 2 and a major cardiac defect in 1, so that no T-21 were missed by the overall screening program. Use of likelihood ratios (LR) from the genetic sonogram to modify the risk of screening tests, resulted in higher detection rates for both 1st and 2nd trimester screens (92% and 93% respectively), and reduced the FPRs to 5.6% and 7.4% respectively. CONCLUSION: The use of likelihood ratios from 2nd trimester genetic sonography improves the performance of 1st and 2nd trimester screens, by significantly reducing the FPR with further increases in detection rates.

Cost-effectiveness model for first-trimester versus second-trimester ultrasound screening for down syndrome

Purpose To develop a cost-effectiveness analysis model from the perspective of Medicare reimbursement to evaluate the costs and potential risks involved in performing second-trimester genetic sonography following the first-trimester sonographic measurement of nuchal translucency and serology for Down syndrome screening. Methods Three clinical screening algorithms were constructed that detailed the diagnostic evaluation of the target population by using first-trimester or second-trimester ultrasound and appropriate serologies or first-trimester and second-trimester screening in combination. The cost analysis was then created by using a computer spreadsheet program by applying Medicare reimbursement, the prevalence of Down syndrome, and reported sensitivities of first-trimester and second-trimester ultrasound and analytes for Down syndrome for each clinical algorithm. Medicare Current Procedural Terminology codes, total relative value units, and payments for first-trimester and second-trimester ultrasound, chorionic villous sampling, amniocentesis, and serum analytes were obtained from the Medicare Part B Washington 2002 Provider Disclosure Report. Results At any given prevalence of Down syndrome, first-trimester screening is always slightly less expensive to society than the other two models for both total cost and cost to diagnose each case of Down syndrome. Even if second-trimester screening were 100% sensitive, the sensitivity of first-trimester screening would have to fall below 55% for model 2 to be cheaper than model 1. Combining both first-trimester and second-trimester screening was substantially more expensive than models 1 or 2. More iatrogenic fetal deaths occur with combined screening than with either first or second trimester screening alone. Conclusions Screening using first-trimester ultrasound and serologic markers to screen for Down syndrome is always slightly less expensive to society than second-trimester serologic and ultrasound screening. However, there is a significantly increased risk for iatrogenic fetal death if second-trimester genetic sonography is performed following normal first-trimester screening using currently accepted risk ratios. Patients should be counseled appropriately with this information, because an individual’s circumstances will affect that person’s perception of risk and subsequently affect his or her decision making.

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.

Is genetic ultrasound cost-effective?

During the past 10 years, investigators have reported studies examining the potential of second-trimester genetic sonography to identify fetuses at risk for trisomy 21. The consensus among most investigators is that genetic sonography offers an alternative to universal amniocentesis in high-risk women and lowers the loss rate of normal fetuses subjected to amniocentesis because of risk factors associated with advanced maternal age or abnormal maternal-serum screening. Although there is now consensus that genetic sonography may be a useful screening tool, there has been a paucity of data regarding its cost-effectiveness. In this review, 3 studies are examined and cost-effectiveness of genetic sonography evaluated. The first study compared genetic sonography and universal amniocentesis and found that genetic sonography was cost-effective if the sensitivity is 75% or higher, resulted in a savings to the healthcare system of 9%, and decreased the loss rate of normal fetuses following amniocentesis by 87%. The second study examined the use of genetic sonography in women less than 35 years of age who underwent maternal-serum triple-marker serum screening. Women who were screen negative but who were classified as moderate risk for trisomy 21 (risk 1:191 to 1:1,000) were offered genetic sonography. Amniocentesis was offered only if the genetic sonogram was abnormal. The study demonstrated that the use of genetic sonography in this group of patients increased the detection rate of trisomy 21, was cost effective, and was a safe procedure. The third study examined the use of genetic sonography in women 35 years of age and older who declined amniocentesis following second-trimester genetic counseling. Genetic sonography was offered to this group of patients followed by amniocentesis if an abnormal ultrasound finding was present. The data were analyzed for various acceptance rates of amniocentesis by the patient when informed of the ultrasound findings. Examination of the data demonstrated this approach increased the detection rate of trisomy 21, was cost-effective, and was a safe procedure. In conclusion, genetic sonography when applied in the above clinical settings is cost-effective, results in a higher detection rate of trisomy 21, and is safe procedure.

P070: A negative second trimester triple test with elevated hCG levels may need second-trimester genetic sonography

P070: A negative second trimester triple test with elevated hCG levels may need second-trimester genetic sonography

Second-Trimester Genetic Sonography in Patients With Advanced Maternal Age and Normal Triple Screen

Second-Trimester Genetic Sonography in Patients With Advanced Maternal Age and Normal Triple Screen

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.

Use of genetic sonography in screening for trisomy 21.

everal studies have been published regarding the accuracy of second-trimester genetic sonography in the prenatal detection of fetuses with trisomy 21. A secondtrimester genetic sonogram is a targeted examination for the presence of fetal structural anomalies as well as other aneuploidy markers, such as short femur, short humerus, pyelectasis, increased nuchal fold thickening, echogenic bowel, hypoplastic middle phalanx of the fifth digit, and sandal gap. By combining multiple sonographic markers and by defining as abnormal any sonographic finding of 1 or more aneuploidy markers, several investigators have achieved detection rates (sensitivities) for fetal trisomy 21 between 60% and 91%. Because of these high detection rates, we as well as others have advocated the use of genetic sonography as an adjunct to maternal age and maternal serum screening to adjust the risk and, therefore, to modify clinical management for patients who are at high risk for fetal trisomy 21. However, there is a paucity of data regarding the impact of such management modification. The article by DeVore and Romero 1 in this issue is a step in the right direction, and it provides invaluable information regarding the impact of genetic sonography as a screening tool for patients younger than 35 years who are at high or “moderate” risk for fetal trisomy 21 after triple-marker screening. The impact of genetic sonography was measured in terms of monetary and nonmonetary benefits, such as total costs, costs per detected fetus with trisomy 21, number of amniocenteses required to identify a single fetus with trisomy 21, and number of fetuses without abnormalities who were lost after amniocentesis.