First-Trimester Sonographic Screening for Down Syndrome

Transcription

1 HIGH-RISK PREGNANCY SERIES: AN EXPERT S VIEW We have invited select authorities to present background information on challenging clinical problems and practical information on diagnosis and treatment for use by practitioners. First-Trimester Sonographic Screening for Down Syndrome Fergal D. Malone, MD, and Mary E. D Alton, MD, for the Society for Maternal Fetal Medicine Screening for Down syndrome is an important part of routine antenatal care. The most common screening method in the United States involves the assessment of a combination of factors: maternal age, multiple secondtrimester serum markers, and second-trimester ultrasonography (as a so-called genetic sonogram ). More recently, however, there has been significant interest in firsttrimester methods of screening, including screening for first-trimester serum markers and the sonographic measurement of fetal nuchal translucency. Multiple studies have demonstrated that fetal nuchal translucency has the potential of being a very powerful predictor of fetal aneuploidy. However, for clinicians a large void remains between this knowledge and the practical issues that must be addressed prior to endorsing this form of screening for widespread use. This article provides an objective assessment of the literature describing nuchal translucency, as well as some adjunct first-trimester sonographic techniques, such as ductus venosus flow and nasal bone studies. Additionally, a detailed description of practical problems that might limit the implementation of this form of screening is presented. (Obstet Gynecol 2003;102: by The American College of Obstetricians and Gynecologists.) Significant advances have been made in antenatal screening for Down syndrome over the past few decades. Initially, invasive prenatal diagnosis for Down From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, Columbia Presbyterian Medical Center, New York, New York. The authors thank L. H. Lumey, MD, MPH, PhD for his contributions to this article. We thank the following individuals who, in addition to members of our Editorial Board, will serve as referees for this series: Dwight P. Cruikshank, MD, Ronald S. Gibbs, MD, Gary D. V. Hankins, MD, Philip B. Mead, MD, Kenneth L. Noller, MD, Catherine Y. Spong, MD, and Edward E. Wallach, MD. syndrome with amniocentesis or chorionic villus sampling (CVS) was offered only to women of advanced maternal age (older than 35 years at delivery) or those who previously had an affected child. Subsequently, invasive diagnosis was offered to women younger than 35 years who had abnormal second-trimester multiple-marker serum screening and also to those with abnormal second-trimester sonographic signs so-called soft-markers of Down syndrome. The most efficient multiple-marker screening test in the second trimester is the quad screen, comprising alpha-fetoprotein (AFP), human chorionic gonadotropin (hcg), unconjugated estriol (E3), and Inhibin-A. This approach yields sensitivities for Down syndrome of 67 76%, depending on whether menstrual or sonographic dating is used, respectively, for a 5% false-positive rate. 1 Most recently, great interest has been directed toward first-trimester screening with the use of new sonographic and serum screening markers. In a recent survey of perinatologists in the United States, 46% used nuchal translucency sonography, and 27% used the serum markers pregnancy-associated plasma protein A and hcg during the first trimester to screen for Down syndrome. 2 The purpose of this review is to summarize the current data that have resulted in a shift toward first-trimester screening and to articulate the implementation issues that need to be addressed before more widespread use of nuchal translucency based screening programs. FETAL NUCHAL TRANSLUCENCY Nuchal translucency refers to the normal subcutaneous fluid-filled space between the back of the fetal neck and the overlying skin (Figure 1). By adhering to a standard ultrasonographic technique, it is possible to obtain accurate measurements of this area in the vast majority of 1066 VOL. 102, NO. 5, PART 1, NOVEMBER /03/$ by The American College of Obstetricians and Gynecologists. Published by Elsevier. doi: /j.obstetgynecol

2 Figure 1. Nuchal translucency ultrasound measurement at 13 weeks in a chromosomally normal fetus, measuring 1.6 mm. Various features of good nuchal translucency ultrasound technique are evident in this image: adequate image magnification, midsagittal plane, neutral neck position, inner-to-inner caliper placement perpendicular to the fetal body axis (as indicated by white arrow), and separate visualization of the overlying fetal skin and amnion. Malone. First Trimester Screening. Obstet Gynecol Figure 2. Increased nuchal translucency measurement of 3.7 mm at 12 weeks in a fetus with Down syndrome. Malone. First Trimester Screening. Obstet Gynecol VOL. 102, NO. 5, PART 1, NOVEMBER 2003 Malone and D Alton First Trimester Screening 1067

3 Sonographic Criteria to Maximize Quality of Nuchal Translucency Sonography 1. Nuchal translucency ultrasound should only be performed by sonographers or sonologists trained and experienced in the technique. 2. Transabdominal or transvaginal approach should be left to the sonographer s discretion, based on maternal body habitus, gestational age, and fetal position. 3. Gestation should be limited to between 10 weeks 3 days and 13 weeks 6 days (approximate fetal crown rump length, mm). 4. Fetus should be examined in a midsagittal plane. 5. Fetal neck should be in a neutral position. 6. Fetal image should occupy at least 75% of the viewable screen. 7. Fetal movement should be awaited to distinguish between amnion and overlying fetal skin. 8. Calipers should be placed on the inner borders of the nuchal fold. 9. Calipers should be placed perpendicular to the long axis of the fetal body. 10. At least three nuchal translucency measurements should be obtained, with the mean value of those used in risk assessment and patient counseling. 11. At least 20 minutes might need to be dedicated to the nuchal translucency measurement before abandoning the effort as failed. fetuses between 10 and 14 weeks gestation. The components of one commonly accepted nuchal translucency sonographic technique are summarized in the box on page These criteria were used successfully in the recently completed First and Second Trimester Evaluation of Risk (FASTER) trial in the United States. There seems to be a direct correlation between increasing nuchal translucency measurement and risk for Down syndrome, other aneuploidies, major structural malformations, and adverse pregnancy outcome. 3,4 Figure 2 demonstrates an increased nuchal translucency observed in a fetus subsequently shown to have Down syndrome. There are several hypotheses regarding the pathophysiology of large nuchal translucency, and it is unlikely that a single common etiology for this sonographic sign underlies all associated abnormalities. Possible etiologies include cardiac failure secondary to structural malformation, abnormalities in the extracellular matrix, and abnormal or delayed development of the lymphatic system. 4,5 NUCHAL TRANSLUCENCY SCREENING FOR DOWN SYNDROME Most early studies of nuchal translucency based screening were performed on patients at high risk for fetal aneuploidy, with sensitivities for Down syndrome ranging from 46% to 62%. 3 These studies were useful in establishing that an association exists between increased nuchal translucency and Down syndrome. However, because they were mostly small, retrospective studies of patients drawn from select high-risk populations, they could not address the role of nuchal translucency measurement in general-population screening. Extrapolation of results from select high-risk populations to generalpopulation screening will overestimate the true performance of a screening test. Methodology To evaluate the current literature regarding the performance of nuchal translucency based screening in the general population, a literature search was carried out with the Ovid MEDLINE search engine (Ovid Technologies, New York, NY), EMBASE 1-4, LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), the University of York National Health Service Center for Reviews and Dissemination Databases, and manual searches of bibliographies of selected publications. The period for the search was from 1966 until April Keywords used included nuchal translucency, Down syndrome, trisomy 21, and prenatal diagnosis. Studies were included if patients were reported as being unselected or from a general population. Case reports and retrospective case control series were excluded, as were studies describing fewer than five cases of Down syndrome. 6 9 When multiple studies described the same population, the most recent publication was selected. Whenever possible, data extraction was limited to the gestational age range of completed weeks. For each study, data regarding prevalence, sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios for Down syndrome were calculated. Pooled estimates for these performance characteristics were also calculated, with the objective being to summarize the current literature on this form of screening. Confidence limits for the test characteristics of the pooled data were calculated for a four-fold table with fixed marginal frequencies. Results A total of 30 studies meeting these criteria were found in which data on the performance of nuchal translucency based screening in an unselected general population 1068 Malone and D Alton First Trimester Screening OBSTETRICS & GYNECOLOGY

4 Table 1. Studies of Nuchal Translucency Screening in Unselected Patient Populations Authors (reference) Number of fetuses Prevalence* Trisomy 21 Sensitivity n (%) FPR (%) PPV (%) LR( ) LR( ) Kornman et al (10) /7 (29) Taipale et al (11) /6 (67) Hafner et al (12) /7 (43) Economides et al (13) /8 (63) Theodoropoulos et al (14) /11 (91) Snijders et al (15) 96, /326 (82) Pajkrt et al (16) /9 (67) DeBiasio et al (17) /13 (62) Quispe et al (18) /7 (100) Whitlow et al (19) /23 (57) Schwarzler et al (20) /12 (83) Thilaganathan et al (21) /21 (76) Krantz et al (22) /33 (73) O Callaghan et al (23) /8 (75) Niemimaa et al (24) /5 (60) Schuchter et al (25) /19 (58) Audibert et al (26) /12 (75) Michailidis et al (27) /23 (83) Gasiorek-Wiens et al (28) 21, /210 (83) Zoppi et al (29) 10, /64 (91) Brizot et al (30) /10 (70) Wayda et al (31) /17 (100) Schuchter et al (32) /14 (57) Murta and Franca (33) /14 (64) Rozenberg et al (34) /21 (62) Crossley et al (35) 17, /37 (54) Lam et al (36) 16, /35 (69) Bindra et al (37) 14, /82 (79) Comas et al (38) /38 (100) Wald et al (39) 39, /85 (63) Total 316, /1,177(77.3) (Pooled 95% CI) (75, 80) (5.8, 6.0) (4.5, 4.8) (12.7, 13.5) (0.22, 0.27) FPR false positive rate; PPV positive predictive value; LR( ) likelihood ratio for trisomy 21 given positive result; LR( ) likelihood ratio for trisomy 21 given negative result; CI confidence interval. * Prevalence of trisomy 21 per 1000 ascertained pregnancies. were available These studies are summarized in Table 1. In combination, these studies describe 316,311 patients who were screened with nuchal translucency sonography during the first trimester. Only one of these studies included patients before 10 weeks gestation. 10 A total of 1177 fetuses with Down syndrome were ascertained in this population, for a prevalence of 3.7 per 1000 pregnancies. However, 11 of these 30 studies had a Down syndrome prevalence of 5 per 1000 or greater, suggesting that these were unlikely to be representative of the general patient population. 10,16 18,22,23,28,29,33,37,38 Such studies likely overstate the true performance of nuchal translucency based screening in the unselected general population. By far the largest of these studies was conducted by Snijders et al 15 of the Fetal Medicine Foundation in London, in which 96,127 unselected patients at 22 centers had nuchal translucency ultrasound performed between 10 and 14 weeks gestation. That series reported sensitivity for Down syndrome of 82% with a falsepositive rate of 8%, which is equivalent to 77% sensitivity for a 5% false-positive rate. However, the calculation of the Down syndrome detection rate in that study has been called into question. Snijders et al 15 calculated that in the absence of any form of screening in their population of 96,127 patients, there would have been 266 live births of infants at term with Down syndrome. This calculation was based on the maternal age and gestational age distribution of the enrolled subjects. However, it is known that as many as 40% of fetuses alive at weeks gestation with Down syndrome will not survive to term, but instead will result in a spontaneous intrauterine demise. 40 Therefore, if 266 infants with Down syndrome were present in a population at term, that would imply that at least 443 fetuses with Down syndrome must have been alive at VOL. 102, NO. 5, PART 1, NOVEMBER 2003 Malone and D Alton First Trimester Screening 1069

5 10 14 weeks gestation, which is the time the screening test was performed (443 times ; 443 minus term live births). Therefore the quoted Down syndrome detection rate of 268 of 326 (82%) should have been more correctly stated as 268 of 443, or 60%. 41 When data from all 30 studies described in Table 1 were pooled, the overall sensitivity for Down syndrome was 77%, with a false positive rate of 6%. The overall odds of carrying a fetus with Down syndrome, given a positive nuchal translucency screen, were approximately 1 in 20 (positive predictive value 4.7%, 95% confidence interval [CI] 4.5, 4.8). There is considerable variability in these studies, however, with sensitivities varying from 29% to 100%, false-positive rates varying from 0.3% to 11.6%, and positive predictive values ranging from 1.6% to 50%. Likelihood ratios express how many times more (or less) a test result is to be found in affected compared with unaffected individuals. As can be seen in Table 1, an abnormal nuchal translucency is 13 times more likely when Down syndrome is present, compared with when Down syndrome is not present (positive likelihood ratio 13.1, 95% CI 12.7, 13.5). A normal nuchal translucency is about one quarter as likely in the absence of Down syndrome (negative likelihood ratio 0.24, 95% CI 0.22, 0.27). It should be noted, however, that these likelihood ratios might be inflated because losses of fetuses with Down syndrome between the time of screening and birth have not been adequately addressed in most of the listed studies. LIMITATIONS OF CURRENT LITERATURE ON NUCHAL TRANSCLUCENCY BASED SCREENING Underascertainment of Cases of Down Syndrome All interventional studies of Down syndrome screening in which there is anything less than 100% karyotype information on all enrolled patients will be subject to underascertainment bias. This is because cases of Down syndrome are more likely to result in demise in utero, and therefore early pregnancy losses and stillborn fetuses are likely to contain significant numbers of cases of Down syndrome. In a review of this topic, in which studies were grouped as being either subject to ascertainment bias or not subject to ascertainment bias, the mean sensitivity for Down syndrome was 77% in the former but only 55% in the latter. 42 Almost all of the studies listed in Table 1 are subject to significant underascertainment bias. Only nine of the 30 studies listed provided sufficient details of study methodology that describe efforts to maximize ascertainment of cases of Down syndrome ,19,20,26,31,36,39 Most studies did not even attempt to obtain pregnancy outcome or karyotype information on cases of stillborn fetus or early pregnancy loss, which are groups likely to contain cases of Down syndrome. As discussed above, underascertainment of true cases of Down syndrome in the large Fetal Medicine Foundation study by Snijders et al most likely masks a true sensitivity somewhere between 60% and 77% for a 5% false positive rate. 15,41 Unfortunately, because of their study design, we can only speculate as to what the true prevalence of Down syndrome was in most of the studies listed in Table 1. Success Rate of Obtaining Adequate Nuchal Translucency Measurement Many studies do not provide any information on the success rate at obtaining a nuchal translucency measurement ,17 19,22 25,27,31,33,38 Some studies suggest a 100% success rate at obtaining a nuchal translucency measurement, 20,28 30,37 but none provide information on the adequacy of these images once obtained. Given that nuchal translucency sonography is very operatordependent, requiring considerable training and experience to master, attention needs to be paid not only to obtaining a measurement, but also to obtaining a satisfactory measurement. Although some investigators who work with the Fetal Medicine Foundation suggest that a 100% success rate at obtaining nuchal translucency sonography is possible, 30,37 this might not be universally attainable. In the multicenter Scottish Trial of first trimester screening, in which nuchal translucency training and quality control was provided by the Fetal Medicine Foundation, one acceptable measurement was obtained in only 73% of cases, and three acceptable measurements were obtained in only 52%. 35 It is inappropriate to quote Down syndrome detection rates based only on the subgroup of patients in which nuchal translucency sonography was successful. Such calculations should be based on all patients who presented for screening. For example, in the Scottish Trial, the sensitivity for Down syndrome was 54% (5% false-positive rate) for patients in whom nuchal translucency was successful but was only 44% when all patients who desired screening were included. 35 Lack of Control Groups for Comparison The current standard for Down syndrome screening in the United States relies on second-trimester multiplemarker serum screening and maternal age. Before this standard can be replaced by a new screening paradigm, novel approaches to screening should be compared with current methods. It is inappropriate to compare firsttrimester screening performance derived from one study with second-trimester screening performance derived from another study, because the prevalence of Down 1070 Malone and D Alton First Trimester Screening OBSTETRICS & GYNECOLOGY

6 Figure 3. Variation in false positive rates for a fixed 85% detection rate for Down syndrome according to the method of screening. NT nuchal translucency; AFP alpha-fetoprotein; hcg human chorionic gonadotropin; PAPP-A pregnancy-associated plasma protein A. Data from Wald et al. 39 Malone. First Trimester Screening. Obstet Gynecol syndrome will necessarily be different between both populations. Only one of the studies listed in Table 1 has any control groups for comparison. 39 Most comparisons available to date for screening performances at different gestational ages are derived from the use of mathematical models and data from multiple studies. Recently completed trials in the United States (FASTER) and the United Kingdom (SURUSS [Serum, Urine and Ultrasound Screening Study]) will for the first time provide such comparative data upon which the range of screening tests currently available can be directly compared. 39 Figure 3 summarizes the comparative performance of the various screening options from SURUSS, which was a recent prospective study in which 98 cases of Down syndrome together with 490 control pregnancies were analyzed. 39 NUCHAL TRANSLUCENCY SCREENING WITH FIRST- TRIMESTER SERUM MARKERS: COMBINED TESTING Research in first-trimester maternal serum screening has consistently shown that pregnancies with fetal Down syndrome are associated with higher levels of total hcg and of the free subunit of hcg (with a median multiple of the median [MoM] of 1.83 in affected cases) and lower levels of pregnancy-associated plasma protein A (with a median MoM of 0.38 in affected cases). 43 Studies of the combination of free subunit of hcg, pregnancy-associated plasma protein A, and maternal age uniformly demonstrate a sensitivity for Down syndrome of approximately 60% with a 5% false-positive rate. 43 This uniformity is in contrast to studies of nuchal translucency in Table 1, which demonstrate significant variability in quoted detection rates. These first-trimester serum markers seem to be independent of nuchal translucency, which would imply that both serum and ultrasound approaches can be combined into a single protocol more effective for screening than either alone. The literature search described above also revealed a total of seven published studies of combined first-trimester serum and ultrasound screening meeting criteria for inclusion in this review. Detection rates for this combined test from the seven studies published to date are summarized in Table 2. With a total of 85,412 patients screened in these studies, the overall sensitivity for Down syndrome was 82% for a 5% false-positive rate. 17,22,24,32,35,37,39 As pointed out above, most of these studies provide minimal information in their methodology sections describing pregnancy outcome ascertainment, and therefore the precision of this estimate of Down syndrome detection is unknown. The positive predictive value for Down syndrome, given an abnormal first-trimester screen, was 5.4% (95% CI 5.1, 5.7). As can VOL. 102, NO. 5, PART 1, NOVEMBER 2003 Malone and D Alton First Trimester Screening 1071

7 Table 2. Studies of First Trimester Combined Nuchal Translucency and Serum Screening Authors (reference) Number of fetuses Prevalence* Trisomy 21 Sensitivity n (%) FPR (%) PPV (%) LR( ) LR( ) DeBiasio et al (17) /13 (85) Krantz et al (22) /33 (91) Niemimaa et al (24) /5 (80) Schuchter et al (32) /14 (86) Crossley et al (35) 17, /45 (62) Bindra et al (37) 14, /82 (92) Wald et al (39) 39, /85 (80) Total 85, /277 (82.3) (Pooled 95% CI) (77, 87) (4.6, 4.8) (5.1, 5.7) (16.6, 18.7) (0.14, 0.24) Abbreviations as in Table 1. * Prevalence of trisomy 21 per 1000 ascertained pregnancies. be seen in Table 2, an abnormal first-trimester screening result is 18 times more likely when Down syndrome is present, compared with when Down syndrome is not present (positive likelihood ratio 17.5, 95% CI 16.6, 18.7). A normal first-trimester screening result is about one fifth as likely in the absence of Down syndrome (negative likelihood ratio 0.18, 95% CI 0.14, 0.24). NUCHAL TRANSLUCENCY SCREENING WITH FIRST- AND SECOND-TRIMESTER SERUM MARKERS: INTEGRATED TESTING Incorporating nuchal translucency and maternal serum markers obtained in the first trimester with maternal serum analytes from the second trimester to provide patients with a single risk assessment has been proposed as an alternative to quoting separate Down syndrome risks in each trimester. This two-step approach, commonly known as the integrated test, involves combining nuchal translucency and pregnancy-associated plasma protein A in the first trimester with serum AFP, hcg, unconjugated E3, and Inhibin-A in the second, with a single Down s risk result being provided in the second trimester. The advantage of this test seems to be a very high sensitivity for Down syndrome, with models suggesting that this might be as high as 94% for a 5% false-positive rate. 44 Alternatively, such an approach could be used to significantly reduce the false-positive rate, to as low as 1%, while maintaining a high sensitivity of 85% (Figure 3). 39 Although integrated testing has been introduced at a few centers, it remains controversial, with concerns about withholding a potentially significant first-trimester finding until after the second-trimester testing has been completed. 45 Although many patients might prefer the speed of having a first-trimester screening test, others might prefer the efficiency and safety of a single screening result that maximizes detection rate while minimizing the false-positive rate. The results of the recently completed FASTER and SURUSS trials will help to evaluate the relative performances of these various approaches to Down syndrome screening and provide some data on patients preferences. NUCHAL TRANSLUCENCY SCREENING AND DUCTUS VENOSUS FLOW IN THE FIRST TRIMESTER In addition to nuchal translucency measurement, firsttrimester sonographic evaluation of ductus venosus flow has been described for aneuploidy screening. Forward biphasic pulsatile ductus venosus flow, as illustrated in Figure 4, is normal, whereas reversed flow at the time of the atrial contraction has been associated with aneuploidy and heart defects. 46 In the studies published to date evaluating this association, between 59% and 93% of aneuploid fetuses had abnormal first-trimester ductus venosus flow velocities Abnormal ductus venosus flow velocities were also found in as few as 3% or as many as 21% of normal fetuses. It has therefore been suggested that after completing a nuchal translucency ultrasound examination, further study of the fetal ductus venosus flow velocity waveform might be useful to modify a patient s risk for aneuploidy. This could be used either to improve the detection rate of nuchal translucency alone or alternatively to reduce the false-positive rate. Although it appears that there is some association between abnormal ductus venosus flow studies and aneuploidy in the first trimester, there are several pitfalls that must be considered. The ductus venosus vessel itself might be as small as 2 mm at weeks, and a typical Doppler gate size might vary from 0.5 to 2 mm. Therefore, it can be difficult to obtain accurate flow velocity waveforms from such a tiny vessel without contamination of the waveform from neighboring vessels. For example, if the Doppler gate is placed too proximally 1072 Malone and D Alton First Trimester Screening OBSTETRICS & GYNECOLOGY

8 Figure 4. Ductus venosus flow velocity waveform in a normal 13 week fetus. The Doppler gate is placed in the ductus venosus between the umbilical venous sinus and the inferior vena cava. Note that there is biphasic pulsatile flow with constant forward flow. The troughs of flow during the atrial contraction also demonstrate forward flow. Malone. First Trimester Screening. Obstet Gynecol near the umbilical sinus, the normal continuous venous flow from the umbilical vein might obscure absence of flow during the atrial contraction in the ductus venosus. Alternatively, placement of the Doppler gate too far distally, near the insertion of the ductus venosus into the inferior vena cava, might lead to the erroneous diagnosis of reversal of flow at the atrial contraction, because such reversal of flow is normal in the inferior vena cava. Furthermore, it is not sufficiently clear yet from published studies of nuchal translucency and ductus venosus flow whether these two sonographic features are in fact completely independent. If they are not fully independent of each other, then it might not be statistically valid to use one test to alter the risk assessment derived from the other test. Based on these concerns, it is currently suggested that first-trimester ductus venosus Doppler flow studies be limited to predicting the prognosis of fetuses with normal chromosomes and an increased nuchal translucency measurement. 52 NUCHAL TRANSLUCENCY SCREENING AND NASAL BONE IN THE FIRST TRIMESTER It has recently been suggested that absence of the fetal nose bone on first-trimester ultrasound screening is associated with increased risk for Down syndrome. 53 In a study conducted by Cicero et al, fetuses with increased nuchal translucency were evaluated for the presence or absence of the nose bone during the first trimester. A nose bone could not be visualized in 73% of Down syndrome fetuses (43 of 59) and in only 0.5% of unaffected fetuses (three of 603). The authors also felt that the absence of the fetal nose bone was not related to nuchal translucency thickness and therefore could be combined into a single ultrasound screening modality, with a predicted sensitivity of 85% for a 1% false-positive rate. 53 This study was challenged by a subsequent report of five consecutive Down syndrome cases, each of which reportedly had a visible nasal bone. 54 However, the five images presented in this latter report do not represent optimal views to evaluate the fetal nose bone. Adequate imaging of the fetal nasal bone can be technically challenging in the first trimester, and careful attention to correct technique should therefore be paid to ensure consistency in technique. The nasal bone should be visualized on ultrasound along the midsagittal plane with a perfect fetal profile. The fetal spine should be down, with slight neck flexion. Two echogenic lines at the fetal nose profile should be visualized; the superficial echogenic line is the nasal skin, and the deeper echogenic line represents the nasal bone. This deeper echogenic line representing the nasal bone should be more echolucent at its distal end (Figure 5). Care should be taken not VOL. 102, NO. 5, PART 1, NOVEMBER 2003 Malone and D Alton First Trimester Screening 1073

9 Figure 5. Nasal bone image of a euploid fetus at 13 weeks gestation. Various features of good nasal bone technique are evident in this image: a good midsagittal plane, clear fetal profile, downward-facing spine, slight neck flexion, and two echogenic lines, representing the overlying fetal skin and the nasal bone. The white arrow represents the fetal nose bone, which loses its echogenicity distally. Malone. First Trimester Screening. Obstet Gynecol to perform this evaluation with the ultrasound beam parallel to the plane of the nose bone, because this might erroneously lead to the conclusion of absent nose bone. General population studies are needed to determine the success rate of adequately imaging the fetal nose bone, to evaluate the independence of nasal bone visualization from nuchal translucency and maternal serum markers, and to determine the feasibility of using this ultrasound marker for Down syndrome screening in the general population. NUCHAL TRANSLUCENCY SCREENING IN MULTIPLE GESTATIONS Prenatal risk assessment for Down syndrome in multiple gestation pregnancies has been quite limited before the advent of nuchal translucency based screening. Maternal serum screening has not been widely utilized in the setting of multiple gestations because of the potential for discordancy between twins and the impact of different placentas on the various analytes. The sensitivity for Down syndrome of the second-trimester serum quadruple test in twins has been estimated at only 47% for a 5% false-positive rate, although this rate will vary depending on whether the pregnancy is monochorionic or dichorionic. 55 It seems that the nuchal translucency distribution does not differ significantly in singleton compared with twin pregnancies, which implies that the Down syndrome detection rates should be similar. The false-positive rate of nuchal translucency screening might be higher in monochorionic twins because some complications unique to monochorionic gestations, such as twin-totwin transfusion syndrome, might present with increased nuchal translucency measurement. 56 Although additional research on the efficacy of this screening method in multiple gestations is still needed, nuchal translucency measurement should at least represent an improvement over serum screening in multiple gestations. Currently, some centers are already using nuchal translucency sonography to assist in selecting fetuses for reduction in higher-order multiple gestations. IMPLEMENTING NUCHAL TRANSLUCENCY INTO CLINICAL PRACTICE Nuchal translucency sonography has pushed prenatal screening for Down syndrome into the first trimester, and might lead to major advances in prenatal care. However, there are several practical issues that must be resolved before this form of screening can be recom Malone and D Alton First Trimester Screening OBSTETRICS & GYNECOLOGY

10 mended for implementation into routine obstetric practice. Nuchal Translucency Quality Control The extent of quality control measures among earlier studies of nuchal translucency screening likely accounts for the large inconsistencies in quoted Down syndrome detection rates. Nuchal translucency ultrasound is extremely operator-dependent and will be a poor technique for general population screening if strict guidelines and ongoing quality control systems are not maintained. 57 In one multicenter study in which adequate training and quality control was not addressed, the overall sensitivity for Down syndrome was only 31%. 57 Appropriate training, adherence to a standard technique, and experience are key to its success as a reliable screening tool. The box on page 1068 summarizes criteria that might help maintain stable and high-quality nuchal translucency sonographic technique. Initial training in nuchal translucency sonography, however, is only one element of the quality control needed to optimize this technique. Systems must also be put in place at each local ultrasound practice to ensure that ongoing quality assurance is maintained. How such ongoing quality control is optimally maintained is unclear. Options include regular review of a sampling of nuchal translucency ultrasound images by an independent evaluator, although this might be quite impractical on a national basis. Another alternative might be to track individual sonographers median nuchal translucency measurements and standard deviations over time. This quality assurance technique has the advantage of being easier to standardize and automate, thereby being more practical for national screening. Another practical problem with nuchal translucency quality control is what to do when an individual sonographer s median measurements drift or image quality deteriorates. How should retraining or correction of errors in technique be applied? Who would be responsible for carrying this out? Should a certification or credentialing system be put in place to ensure that only those with adequate training perform this type of screening? Who should administer such a system? What should be done if an individual sonographer s images do not improve despite retraining? Leadership at a national basis is clearly needed to adequately address each of these implementation issues. Nuchal Translucency Interpretation Mean nuchal translucency measurements increase by approximately 17% each week from 10 to 14 weeks gestation. 58 Therefore, it is inappropriate to use a single millimeter cutoff to define an abnormal nuchal translucency or a pregnancy that warrants invasive fetal testing. More appropriate options include using the 95th percentile for a particular gestational age or MoMs. Unfortunately, such cutoff values are not easily available in the published literature, and all require a software program to adequately integrate other background data, such as maternal age, into the risk assessment. The validation of such commercially available software programs in specific populations is also uncertain at this time. For example, it is still unclear whether it is valid to use generic population medians to interpret nuchal translucency measurements or whether such medians for risk calculations should be center-specific or sonographer-specific. In one study that addressed the importance of differences in center-specific medians, a Scottish trial of 15 centers evaluating 17,229 patients had individual center nuchal translucency median MoMs ranging from 0.7 to 1.4 MoMs. 35 Ideally the median MoM should be 1.0. The consequences of such large variability in MoMs between centers could be dramatic. The Down syndrome risk quoted to a 37-year-old patient with a nuchal translucency measurement of 1 mm might vary up to five-fold by having nuchal translucency MoMs that range from 0.7 to 1.4, with quoted risks ranging from 1:1400 to 1:285. Further studies are needed to evaluate the role and feasibility of center-specific or sonographerspecific medians in a national Down syndrome screening program. In the recently completed SURUSS trial from the United Kingdom, the use of sonographer-specific medians resulted in an improvement of 5% in overall Down syndrome detection rates, compared with use of center-specific medians. 39 Implications for Second-Trimester Serum Screening Implementing a national nuchal translucency screening program in isolation will likely have a negative impact on current second-trimester serum screening programs, because the positive predictive value of second-trimester screening might be reduced as much as six-fold after first-trimester screening. 59 The number of fetuses with Down syndrome still alive during the second trimester will be significantly reduced because many such fetuses will have already been diagnosed in the first trimester. Sequential screening without appropriate modifications of second-trimester serum marker cutoffs might increase the overall false-positive rate, resulting in an increased number of amniocenteses and procedure-related pregnancy losses. 60 Furthermore, sequential screening introduces two independent risk results, which might create unnecessary confusion and anxiety for the patient. 61 The only way to adequately ensure against such inefficiency is to either provide a single integrated risk result from both trimesters or to modify the second trimester risk VOL. 102, NO. 5, PART 1, NOVEMBER 2003 Malone and D Alton First Trimester Screening 1075

11 cutoffs to allow for prior first-trimester screening. It is unclear how such risk modification arrangements can be implemented if first-trimester screening is implemented in an uncoordinated manner. Another approach to avoid confusion between uncoordinated first- and second-trimester screening programs would be to drop second-trimester serum screening entirely. However, if Down syndrome screening is limited to the first trimester only, there will likely be a negative impact on neural tube defect detection, which relies on second-trimester maternal serum AFP evaluation. Maternal serum AFP is of no value in the first trimester. Therefore, to drop it completely from antenatal care programs might lead to more cases of spina bifida being missed prenatally. Furthermore, a large proportion of prenatal patients do not present for prenatal care early enough in pregnancy to avail of first-trimester screening. Therefore, second-trimester maternal serum screening will likely remain useful. Currently, second-trimester multiple-marker serum screening is supported by a well-established and successful quality assurance program. It is unclear what the format of a first-trimester sonographic screening quality assurance program would look like. This uncertainty will add to the difficulty in simply dropping second trimester serum screening. Implications for Second-Trimester Ultrasound Nuchal translucency screening will not obviate the need for second-trimester ultrasound for the detection of structural fetal abnormalities. The genetic sonogram, which evaluates for structural malformations and a range of second-trimester soft markers for aneuploidy, such as short femurs, echogenic bowel, echogenic intracardiac foci, and nuchal fold, has gained widespread acceptability. A national policy of first-trimester screening will likely have a negative impact on the performance of the genetic sonogram. The positive predictive value of these ultrasonographic soft markers for aneuploidy will decrease because the number of aneuploid fetuses entering the second trimester will be reduced. It is currently not known what the relevance of these soft markers will be in a population of fetuses that has already undergone nuchal translucency based screening. If the genetic sonogram continues without allowance for the lower prevalence of second-trimester aneuploid fetuses, it is likely that more unnecessary amniocenteses will be performed without significant improvement in detection rates. Availability of Early Prenatal Diagnosis One of the most compelling arguments in favor of nuchal translucency based screening for Down syndrome is the shift to earlier diagnosis through CVS at weeks gestation. Chorionic villus sampling is not as widely available as amniocentesis on a national basis. 2 Early amniocentesis in the first trimester is no longer considered an acceptable alternative to CVS due to its higher association with fetal loss, fetal clubfoot, and procedure failure. 62 If first-trimester screen-positive patients do not have ready access to CVS, they might experience increased anxiety, waiting 3 to 4 weeks for an opportunity to undergo amniocentesis at 15 weeks. Therefore, a policy of first-trimester screening for aneuploidy should not be implemented unless first-trimester diagnosis with CVS is locally available. If a patient desires the benefit of first-trimester screening, but CVS is not easily available, then the optimal approach might be to provide the first-trimester result at 16 weeks as part of a single integrated screening result in combination with second-trimester serum markers. Choosing the Correct Combination of Screening Tests With the increasing range of Down syndrome screening tests available to obstetric providers today, there is a need for accurate comparative data to evaluate the best combination of tests to implement into practice. Figure 3 summarizes the likely comparative performance of each type of screening, by fixing each test at an 85% Down syndrome detection rate. 39 These data were derived from the recently completed SURUSS trial in the United Kingdom and are based on a total of 98 Down syndrome pregnancies and 490 matched controls. These results would suggest that the most inefficient test, associated with the highest screen-positive rate, is nuchal translucency sonography performed on its own. First-trimester screening seems to derive much of its efficiency by combining nuchal translucency with pregnancy-associated plasma protein A and free subunit of hcg evaluation. An integrated screen, incorporating nuchal translucency and pregnancy-associated plasma protein A in the first trimester, together with AFP, hcg, unconjugated E3, and Inhibin-A in the second trimester, seems to be the single most efficient test. In a center without easy access to high-quality nuchal translucency sonography, another reasonable alternative might be a serum-only test, incorporating pregnancy-associated plasma protein A in the first trimester with AFP, hcg, unconjugated E3, and Inhibin-A in the second trimester, with a single risk being quoted. The comparative performance characteristics of this complex array of screening tests remains uncertain. The results of the FASTER trial in the United States will provide precise data upon which to judge the constituents of the optimal screening program for national implementation Malone and D Alton First Trimester Screening OBSTETRICS & GYNECOLOGY

12 Appropriate Patient Counseling Informed consent regarding the variety of prenatal screening tests for aneuploidy should be an integral part of the screening process itself. Because of the complexity of choices regarding the different screening options, and because of the range of abnormal outcomes associated with increased nuchal translucency, it will be vital to provide all patients with pretest genetic counseling before embarking on these newer forms of screening. Some patients might be most interested in the earliest possible screening result; for such patients, combined first trimester nuchal translucency and serum screening might be desired. Other patients might be most interested in the most efficient test, maximizing their detection rate and minimizing the need for amniocentesis; for such patients, a single integrated screen result combining first- and second-trimester approaches might be desired. Still other patients might not present for care sufficiently early to take advantage of first-trimester screening; for these patients, there should be the option of second-trimester serum screening and genetic sonography. CURRENT AND FUTURE STATUS OF NUCHAL TRANSLUCENCY SCREENING IN THE UNITED STATES From a review of the current literature, it seems that nuchal translucency sonography is a powerful prenatal screening tool. However, comparative data with other screening tests are limited. The limited comparative data available would suggest that if first-trimester screening is implemented, the only test that should be recommended at this time is combined nuchal translucency with firsttrimester serum. Nuchal translucency screening alone should not be performed in singleton pregnancies, because it seems to be inferior to either first-trimester combined screening or second-trimester quad marker screening. 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