One of the greatest challenges in prenatal diagnosis is to reduce the loss of fetuses from invasive procedures without compromising the detection rate of abnormal fetuses. Second-trimester maternal serum biochemistry and genetic sonography have been proposed by various investigators as means of adjusting the risk for Down syndrome, and therefore the need for amniocentesis.1–6 In our institution, there is an ever-increasing proportion of women with advanced maternal age who prefer to have a genetic sonogram and triple screen as risk modifiers to potentially avoid amniocentesis.4 Most of these pregnant women with advanced age decide against amniocentesis if both triple screen and genetic sonography are normal. However, there are only few data regarding the usefulness of genetic sonography in the presence of advanced maternal age and normal triple screen. Therefore, we undertook this study to determine the value of second-trimester genetic sonography in detecting fetal Down syndrome in patients with advanced maternal age and normal triple screen.
MATERIALS AND METHODS
From November 1, 1992, through June 2001, we have offered a second-trimester genetic sonogram to all women who are at high risk for fetal Down syndrome (at least 1:274) and desire a possible risk reduction by means of a normal genetic sonogram. The main indications for genetic sonography (advanced maternal age [at least 35 years], abnormal triple screen, or both) are routinely recorded in our computerized ultrasound database. Our patient population consists of 45% non-Hispanic whites, 35% Hispanic, 15% blacks, and 5% oriental or other. Since July 1999, it became our standard practice to encourage patients scheduled for genetic sonography, as well as their referring private physicians, to obtain a triple screen and provide a copy with the results upon presentation for the genetic ultrasound examination. If the patient or physician failed to provide a copy of the triple screen results, a sonographer or a clerk was instructed to call the referring physician's office and request a faxed copy of the triple screen report. We were able to capture and record the triple screen results of approximately 60% of all patients with advanced maternal age presented for genetic sonography after July 1999; approximately 30–40% of patients with advanced maternal age, who were seen in our ultrasound unit for genetic sonography, did not have triple screen performed, or we were not able to obtain the records from the referring physicians' offices. The overwhelming majority of the triple screens (approximately 90%) were performed in two commercial laboratories (Lab Corp, Burlington, North Carolina and Quest, Teterboro, New Jersey) because of contractual reasons with managed care organizations.
The study was approved by the Institutional Review Board. The financial support for this study was provided by our Department of Obstetrics, Gynecology, and Reproductive Sciences.
The method used to perform genetic sonography has been previously described.3,4 The genetic sonograms are performed by an experienced sonographer or a maternal-fetal medicine fellow and also a maternal-fetal medicine attending physician. In addition to the basic ultrasound fetal biometry, the following fetal aneuploidy markers were assessed: facial (clefts, nose, orbital) anomalies, hand anomalies, cardiac anomalies (four-chamber view as well as both outflow tracts), short long bones (femur, humerus, tibia, fibula), pyelectasis, nuchal fold thickening at least 6 mm, echogenic bowel, choroid plexus cysts at least 10 mm, echogenic intracardiac focus, clinodactyly, sandal gap, and two-vessel umbilical cord. In approximately 7% of the patients, the fetal face or heart was not adequately visualized. For the purpose of this study, such sonograms were considered “normal” in the absence of any other sonographic findings. The patients were counseled immediately after the sonogram. Those who desired to proceed with a genetic amniocentesis had the procedure done immediately or within a few days. Outcome information was obtained by reviewing the results of genetic amniocentesis, if performed, or by contacting the patient or the pediatrician after birth.
Statistical analysis included descriptive statistics, and analysis was based on the Fisher exact test. A P value < .05 was considered significant, and all tests were two-tailed.
A total of 959 patients with advanced maternal age, singleton fetus, and normal triple screen results were identified. Outcome information was obtained for 768 patients (155 pregnancies are ongoing at the time of this writing, and 36 were lost to follow-up). In the cases with known outcome, the maternal age (median) was 36 years (range 35–57). The median risk for fetal Down syndrome based on maternal age was 1:213 (range 1:37–1:274). The median risk for Down syndrome based on triple screen results was 1:1069 (range 1:275–1:40,000). The observed prevalence of fetal Down syndrome was 0.52% (4 of 768 or 1:192). The observed prevalence of Down syndrome (1 in 1:192) was similar to that expected based on maternal age (1:213), but it was higher than expected based on the triple screen results (1:1069).
Of the 768 patients, 673 had normal genetic sonography, and none (0%) had Down syndrome; 95 patients had abnormal genetic sonography (one or more aneuploidy markers present), and four (4.2%) had fetuses with Down syndrome (P < .001). As shown in Table 1, the triple screen risks for these four fetuses ranged from 1:319 to 1:833, and three of these four fetuses had at least two aneuploidy markers present. Of the 91 fetuses with abnormal sonogram and no aneuploidy, eight were found to have the following anomalies: atrial septal defect (two), atrioventricular septal defect (one), hydrocephalus (one), left renal agenesis (one), bilateral club feet (one), absence of fourth toe (one), and persistent right umbilical vein (one).
Over the last decade, there have been several studies published regarding the use of second-trimester genetic sonography in the prenatal detection of fetuses with Down syndrome. Second-trimester genetic sonography is a targeted examination of the fetus for the presence or absence of aneuploidy markers, the results of which can be used to adjust the a priori risk for Down syndrome. By combining multiple aneuploidy markers and by defining as abnormal any sonogram with one or more markers, we, as well as other investigators, have achieved detection rates of fetal Down syndrome greater than 80%.3–11 Because of our high detection rate, we have offered 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 21.3,4
Because there is an ever-increasing proportion of pregnant patients with advanced maternal age who seek reassurance from a normal triple screen combined with a normal genetic sonogram, we sought to determine the value of genetic sonography in this setting. We found no cases of fetal Down syndrome among women with advanced maternal age and normal genetic sonography. This finding was not surprising given the high (over 80%) sensitivity of genetic sonography to detect fetal Down syndrome in our institution. However, we identified some striking findings. First, the observed prevalence of fetal Down syndrome in our population sample corresponded to the expected based on maternal age rather than the triple screen results. Therefore, it appears that the prevalence of Down syndrome was underestimated by the triple screen in our pregnant women with advanced maternal age. Secondly, the triple screen risks in patients with fetal Down syndrome were from 1:319 to 1:833, a range which has been recently categorized by DeVore and Romero as “moderate” risk (1:190–1:1000).11 Thirdly, all four fetuses with Down syndrome were detected by genetic sonography and, as shown in Table 1, three of these four fetuses had at least two aneuploidy markers present.
At this point, it should be emphasized that one of the shortcomings of our study is the small number of cases with fetal Down syndrome. However, a post hoc power analysis indicated that our study had a power of 91% (α error 0.05). Thus, this preliminary study suggests that patients with advanced maternal age and normal second-trimester genetic sonography carry very little risk for fetal Down syndrome, and that the use of genetic sonography may increase the detection rate of fetal Down syndrome especially in those with moderate triple screen risks. Future studies including a larger number of patients are needed to confirm the utility of second-trimester sonography in patients with advanced maternal age and normal triple screen. In addition, larger studies are needed to address the observation that triple screen risks may underestimate the actual risks for Down syndrome in the presence of advanced maternal age.
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