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Down syndrome is the most common chromosomal abnormality among live-born infants and a major cause of mental retardation. In addition to having a low IQ, half of those with the disorder have cardiac defects, reducing life expectancy to about 50 years. Prenatal screening allows expectant parents to determine whether their fetus has Down syndrome. Whether they decide to terminate an affected fetus or not, pre-delivery knowledge of the diagnosis appears to convey significant long-term psychological benefits.
There are available strategies for determining the risk of fetal Down syndrome in the second trimester. One option is to offer all women aged 35 and older amniocentesis or chorionic villous sampling (CVS) and to use maternal age and biochemical screening in combination to identify women under age 35 who are at increased risk. Optimal second-trimester biochemical screening employs the "Quad Screen": maternal serum inhibin A, alpha-fetoprotein, estriol and ß-hCG.1 Universal application of this approach would theoretically detect all Down's fetuses in women aged 35 and older, who account for 40% of cases, and at least 60% of Down's cases among those younger than age 35. However, since 11% of pregnancies in the United States now occur in women older than 35, the theoretical "screen-positive" rate of this option approaches 15% for the entire population. (Translation: Amniocentesis needs to be offered to one in 7 pregnant women!)
An alternative second-trimester screening option is to assign risk based on maternal age and biochemical screening in all patients. Applying this option universally would detect 67% to 76% of Down's fetuses for a 5% screen-positive rate.1 For women 35 and older, at least 85% of Down's fetuses would be detected for a 25% screen-positive rate, while at least 60% of Down's fetuses would be detected among women younger than 35 for a 5% screen-positive rate.2 Thus, this second option would identify fewer Down's fetuses among women 35 and older but reduce their need for amniocentesis by 75%. Since the risk of pregnancy loss with amniocentesis is on the order of one per 200 procedures, option two would theoretically prevent 1,650 miscarriages each year in the US. Of course, these figures assume universal acceptance of screening; currently about two thirds of women accept such screening. In addition, some centers offer "genetic ultrasounds" in the second trimester to further refine risks, but it is unclear to what extent this approach affects sensitivity and screen positive rates.3
The desire by prospective parents and their doctors to have earlier diagnoses has led to first-trimester screening initiatives. Nuchal translucency (NT) measurements exploit the tendency of Down's fetuses to have increased subcutaneous fluid in the back of their necks at 10 to 14 weeks. A review of 30 published studies suggests that NT measurements generate an average Down's detection rate of 77.3% with a 5.9% screen-positive rate.4 However, many of these studies were conducted at highly specialized centers. Indeed, while consistent and reliable NT measurements require rigorous training and continuing quality assurance, in one study, only 73% of patients had successful NT measurements despite such training.5 Moreover, this multicenter study observed considerable inter-center variation in average NT measurements, a phenomenon that could lead to considerable variability in detection and screen-positive rates across centers. The recently completed First and Second Trimester Evaluation of Risk (FASTER) trial even observed significant inter-observer variability in NT measurements and noted that NT screening efficacy declined between 11 and 14 weeks, suggesting the test should be performed at 11 weeks.6
In addition to NT measurements, first-trimester maternal serum screening for Down syndrome with the free ß-subunit of hCG and pregnancy-associated plasma protein A (PAPP-A) yields a 60% detection rate (5% screen-positive), though the FASTER study suggests that the efficacy of PAPP-A also declines between 11 and 14 weeks.7 Since these serum markers and NT are independent predictors of risk, they can be combined. In a review of seven published studies involving over 85,000 patients, Malone and D'Alton observed an 82.3% (95% CI, 7787) detection rate for a 4.7% (95% CI, 4.64.8) screen-positive rate for the combination of ß-hCG, PAPP-A, and NT.
There is also evidence that combining first- and second-trimester screening may yield optimal results. The recently completed United Kingdom's Serum, Urine, and Ultrasound Screening Study found that the combination of first-trimester NT and PAPP-A measurements with second-trimester Quad screen resulted in the best testing efficacy, with an 85% detection rate and an incredibly low 1% screen-positive rate.8 This approach in theory could reduce amniocentesis-related miscarriages to 200 per year, or a fivefold reduction from the "safest" second-trimester approach.
At this year's annual meeting of the Society of Maternal Fetal Medicine, Dr. Fergal Malone presented the results of the FASTER trial.6 This study, which involved over 37,000 patients, compared the relative efficacy of first- and second-trimester screening and assessed the relative usefulness of sequential (acting on each data set sequentially) versus integrated (using a combination of both first- and second-trimester data to assign risk) assessment. Between 10 weeks 3 days and 13 weeks 6 days, NT, PAPP-A, and ß-hCG measurements were obtained. A Quad screen was then performed at 15 to 18 weeks. The first-trimester protocol detected 76% of cases for a 3.2% screen-positive rate, the second-trimester approach detected 84% of cases (8.4% screen-positives), and the sequential test detected 94% of cases (11% screen-positives). The optimal approach appeared to be a fully integrated screening protocol including 11-week NT and PAPP-A and 16-week QUAD testing, which detected more than 80% of cases for a very low 1.4% screen-positive rate or more than a 90% detection rate for a 5.4% screen-positive rate. Besides its lower screen-positive rate, integrated screening would eliminate the need for having CVS available, although it would delay some diagnoses by 5 weeks.
Thus, there's overwhelming evidence for adoption of an integrated Down syndrome screening approach in this country, but we'll have to overcome many serious obstacles before this approach can be implemented. The major hurdle is the need for highly trained personnel to take the NT measurements, as well as a method of certification and continuing quality assurance to ensure that precision does not wane over time. In addition, center- or even sonographer-specific risk calculations may be required, given the apparent wide variability in average measurements. Moreover, because an elevated NT measurement in a euploid fetus is a risk factor for fetal demise and cardiac, abdominal wall, and musculoskeletal defects, screening programs must include follow-up anatomical scans and echocardiography at 18 to 20 weeks. In addition, the added benefit of newer first-trimester sonographic markers, such as absence of the nasal bone and Ductus venosus Doppler flow profiles, needs to be assessed.
It is also unclear whether all women will be willing to wait the extra 4 to 5 weeks required between the NT and PAPP-A measurements and the Quad screen. For those who do not want to wait, sequential screening would seem the best option, with CVS for initial screen-positive patients and amniocentesis for later positives. Second-trimester screening (with or without genetic ultrasound) would remain available to women who are late in seeking out prenatal care.
1. Wald NJ, Kennard A, Hackshaw A, et al. Antenatal screening for Down's syndrome. J Med Screen. 1997;4:181-246.
2. Haddow JE, Palomaki GE, Knight GJ, et al. Prenatal screening for Down's syndrome with use of maternal serum markers. N Engl J Med. 1992;327:588-593.
3. Smith-Bindman R, Hosmer W, Feldstein VA, et al. Second-trimester ultrasound to detect fetuses with Down syndrome: a meta-analysis. JAMA. 2001;285:1044-1055.
4. Malone FD, D'Alton ME, Society for Maternal-Fetal Medicine. First-trimester sonographic screening for Down syndrome Obstet Gynecol. 2003;102:1066-1079.
5. Crossley JA, Aitken DA, Cameron AD, et al. Combined ultrasound and biochemical screening for Down's syndrome in the first trimester: a Scottish multicenter study. BJOG. 2002;109:667-676.
6. Malone FD, Wald NJ, Canick JA, et al. First- and Second-Trimester Evaluation of Risk (FASTER) Trial: principal results of the NICHD multicenter Down syndrome screening study. Am J Obstet Gynecol. 2004;189:S56. Abstract 1.
7. Canick JA, Kellner LH. First trimester screening for aneuploidy: serum biochemical markers. Semin Perinatol. 1999;23:359-368.
8. Wald NJ, Rodeck C, Hackshaw AK, et al. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine, and Ultrasound Screening Study (SURUSS). J Med Screen. 2003;10:56-104.
Charles J. Lockwood, MD
Charles Lockwood. Editorial: Screening for Down syndrome: Is FASTER better?
Mar. 1, 2004;49:11, 12.